Ph.D Evelyne Micollier
email: evelyne.micollier@ird.fr

From epistemology to the method: phenomenology of the body, qı cultivation(qıgong) and religious experiences in Chinese worlds

Keywords: body ecologic, phenomenology, qı cultivation, religious experience, Chinese world

At the intersections of social anthropology, philosophy, and Asian studies, my article explores the body ecologic through a phenomenological frame in the context of Chinese culture engaging both theory and method. How can qı cultivation experiences transporting bodies and persons in movement, Within the world and their "life-world", be interpreted through a phenomenology of perception? Based on ethnographic study data collected mainly in South China (Guangzhou) and in Taiwan (1990s-2000s), this exploration is situated within qıgong experiences (training, cultivating and mastering the qı). Anchored in martial, religious, and healing arts and their meanings, qıgong's myriad of forms and infinite variations invite journeys into religious Daoist and Buddhist practice, Chinese thought, and politico-religious issues of past and present Chinese society. The qıgong world, paths of knowledge transmission, healing horizons, claimed affiliations, and views of practitioners unveil an ontology and a cosmology grounded in religious (Daoist and Buddhist) lore.

Qıgong can be translated as "training, cultivating, mastering, art of qı" and qı as "breath, breathing, vapors, influences, vital forces, vitality." Elaborated sets of qıgong practices aim at health preservation, alleviation of pathological states, and the development of the person involving a constellation of martial, therapeutic, religious and social experiences (Micollier 1996). On the one hand, via various forms and techniques inherited from old practices, qıgong immerged into Chinese thought, culture, and experiences.

On the other hand, extra-Western biologies and epistemologies, modern healthcare, and science interplayed with the world of qıgong because elements of Western biology and medicine were re-appropriated within it. The term qıgong was first mentioned in medical sources from early 20th century China: qıgong was used in sanatoriums for treatment and care of tuberculosis [START_REF] Chang | Qı gong yici de youlai (The origine of the word)[END_REF]. Although it is a by-product of encounters with Western science and health policy, this very experience is also transported into a remote history. In our situated study, how can qı cultivation experiences engaging bodies and persons in movement within the world and their "life-world" be interpreted through a phenomenology of perception from epistemology to the method? Instead of drawing on worldviews of individuals and groups, the anthropologist tentatively offers to the gaze the "life-world" of a people, namely "the unquestioned, practical, historically conditioned, pre-theoretical and familiar world of people's everyday lives" (Desjarlais and Throop 2011: 91). Located between knowledge theories and empirical studies of experiences, how do phenomenologies in anthropology shed light on extra-Western phenomenologies and feed the intercultural dialogue in a process of knowledge co-construction?

These research questions open lines onto promising vistas. One line immerges in phenomenology as theory and method in situated contexts opening the doors of qıgong practitioners and the ethnographer experiences. Using the frame of a phenomenology of the body, these are defined for our purpose as an insightful case of human growth through qı cultivation, healing, and bodily religious (Daoist and Buddhist) experiences. The discussion focuses on interlaces between empirical experience, consciousness, and the body ecologic in Chinese worlds. From encounters between tenets of Europe and East Asian phenomenology, as well as from qıgong, its practitioners, forms, and actors, similar intrinsic kaleidoscopic realities are reflected and made available.

Phenomenology as a theory and a method [START_REF] Husserl | The Crisis of European Sciences and Transcendental Phenomenology[END_REF][START_REF] Husserl | The Crisis of European Sciences and Transcendental Phenomenology[END_REF]) first introduced the concept of "life-world" drawing on the concept of "Being-in-the-world" or "toward the world" of [START_REF] Heidegger | Being and Time[END_REF][START_REF] Heidegger | Being and Time[END_REF]), a metaphoric substitute for terms such as the subject and object, the world and consciousness comprehended together. Merleau-Ponty questions "being toward the world" relying on experience, lived life and sensibility, and praising a knowledge of the world through intuitive, rather than inductive or deductive, decision-making as the active process, and logical operations underpinning scientific reasoning. "Being toward the world" is the only possible path to understand phenomena for the "beings"-inhabitants of the world, whose essence is existence (Heidegger 1979) and whose ontological status and action capability vary along positions, and in contrast to others [START_REF] Descola | Beyond Nature and Culture[END_REF]. In this context, the only way to understand that phenomenon is a description of "things as they are" (Merleau-Ponty 1962), e.g. in perpetual transformation, observable and felt in particular spatiotemporal conditions. Regarding the knowledge horizon, Merleau-Ponty suggests refraining from using theoretical and methodological pre-constructed models. Knowledge processing is, before everything else, an experience.

Phenomenological horizons in anthropology and East Asian contexts

Confirming the vitality of engagement with phenomenology in anthropology, recent works [START_REF] Desjarlais | Phenomenological Approaches in Anthropology[END_REF]Ram, Houston and Jackson eds. 2015; Laplante and Sacrini eds. 2016) aim at understanding better how phenomenological horizons can be heuristically used in social anthropology in terms of theory and method. Ram and Houston (2015: 1) suggest a pragmatic definition of phenomenology and elucidate in a nutshell its generic application in anthropology: "phenomenology is an investigation of how human beings perceive, experience, and comprehend the sociable, materially assembled world that they inherit from infancy and in which they dwell. Framed in this way, phenomenology in anthropology is a theory of perception and experience." A number of East Asia scholars, more specifically philosophers, have shown a keen interest in phenomenology from the 1920s: "Even though the Asia-Pacific Region is geographically far away from the birthplace of phenomenology, the development of phenomenology already had its impact on this area as early as the 1920s. Moreover, the Kaizo articles of Husserl were first published in Japanese long before they were published in their original language" (Yu 2010: 1). Husserl had Japanese students in Europe who brought back his writings to Japan.

Nonetheless, today contemporary Chinese scholars refer to phenomenology as a pillar in their work (among them, Yu Chung-chi;Lau Kwok-Ying;Huang Kua-Min;and Jiang Dandan. In Ni, Fang, Lee, and Tani 2015). Key academic institutions in Asia support works engaged in phenomenological approaches. Among these institutions, the Institute of Philosophy and the Center for the Humanities of the National Sun Yat-Sen University (Taiwan), and the Edwin Cheng Foundation Asian Centre for Phenomenology of the Chinese University of Hong Kong are very active in organizing international conferences and other activities. At least ten key organizations in East Asia are identified as developing activities and works in a claimed affiliation with phenomenology. Therefore, phenomenological thought has been re-appropriated and "localized" or "indigenized" over one century in East Asia. This "epistemological turn," developed in multiple trends, shows an impressive vitality today. In this intercultural dialogue dating back to the birth of phenomenology in Europe, the reverse influence from Asia to Europe is poorly documented and barely claimed. For instance, Heidegger's thought has been connected with Daoism (P€oggeler 1987;[START_REF] Parkes | Heidegger and Asian Thought[END_REF][START_REF] May | Heidegger's Hidden Sources: East Asian Influences on His Work[END_REF][START_REF] Ma | Heidegger on East-West Dialogue: Anticipating the Event[END_REF][START_REF] Zhan | Worlding Oneness. Daoism, Heidegger, and Possibilities for Treating the Human[END_REF], and Heidegger had read the Daode jing (Laozi) and even ordered a translation in German [START_REF] Hsiao | Heidegger and Our Translation of the Tao Te Ching[END_REF]. However, he rarely publicly referred to this Daoist influence on his ideas and work. Specifically, he publicly did so only twice in 1958 (see May preface 1996, vii), though he never mentioned it in his writings [START_REF] Chen | How Taoist Is Heidegger?[END_REF]. Precise reference to Daoism cannot be found in Heidegger's philosophical works. Among other Japanese scholars, Hirota's works (2008Hirota's works ( , 2010Hirota's works ( , 2014) ) provide a meaningful appropriation of the philosophy of phenomenology. For instance, there are emphasized resonances among the late Heideggerian notion of "dwelling," the subject/object deconstructing process and the status of truth, and ideas encountered in Pure Land Buddhism's (Jıngtǔ zong) theory. Four characteristics of "dwelling," namely stability, freedom, joy, and proximity, have been discussed by Shinran (Hirota 2014). Jıngtǔ zong is a lay form of Buddhism born in China (3rd Century A.C.) later disseminated in Korea and Japan (eleventh century A.C.). Shinran's thought greatly contributed to "localize" Jıngtǔ Buddhism in the context of Japanese culture (Jodo Buddhism), providing another interpretation of original Chinese texts.

Methodological horizons

Phenomenological seeds enable the ethnographer to grow amazing and unknown plants in the process of framing, reframing, and deframing theoretical canvases from a methodological move based on the description of "things as they are" and the awareness, or consciousness, of "being toward the world." Through participant observation in these contexts, the ethnographer develops a sensibility and an intuitive knowledge while deconstructing a methodological and theoretical frame, if one exists, in order to first see "things as they are." Recognizing it or not, the researcher is often forced to do so during the fieldwork period. In a process of auto-construction, the method is transported, deframed, and (re)shaped by events and experiences in situated contexts. Therefore, describing what is happening (phenomena) and what is lived (experience) subsequently becomes obvious. Field study cannot be dissociated from data processing and analysis because the method is alive in a process of self-construction and is experienced as the ethnographer's "lived-body" [START_REF] Leder | Medicine and the Paradigms of Embodiment[END_REF]. Capturing and building on experience, the ethnographic frame is ever transformed and enriched and the temporal engagement of the research is hence transformed. Anthropological method is hence a "real life method" (Ingold 2014). The anthropologist faces an experience of situational and situated complexity, either observed or observable, and cannot escape from an emergence in situ of the method and from connecting it immediately to the analysis. These engagements are often criticized by other sciences claiming for the relevance of experiment and data collection based on precise pre-constructed protocols. However, a pre-constructed protocol, which does not open onto other horizons in the research process, is experienced by the anthropologist as a locked door on the collection of probable more consistent data through the "opening" and reframing process. These "missing" data may strongly impact the quality of results and the research relevance as a whole. Intrinsically engaged with phenomenology, the anthropological method reflects reciprocal exchanges between philosophy and anthropology. Though anthropologists and philosophers raise the same issues, the former enrich critical and controversial research issues with results from empirical study data, while the latter feed or produce discussion and debates with various methodological and epistemological perspectives. Rather than the legitimacy of discourses (those either of interlocutors' or performative), a phenomenological approach reinforces the legitimacy of observing, located at the heart of the ethnographic method through a specific spatial and temporal frame recalling "situated contexts" favored by historians of the present in their round trips between past and present. Phenomenology as a method subsequently tends to minor the relevance of interviews and material items such as documents and objects. Therefore, pillars of the method lie and rely on observing and other tools mediatizing experience rather than the relevance of words from discourses.

My own study data are drawn from longitudinal anthropological research about qıgong experiences. They were collected through multisited ethnography [START_REF] Marcus | Ethnography in/of the World System: The Emergence of Multi-Sited Ethnography[END_REF] in the 1990s and supplemented with additional items using tools from other investigations. Fieldwork was conducted in China (Guangzhou) in 1991(Guangzhou) in , 1992(Guangzhou) in , and 1999;;in Taiwan (Taipei) from 1995to 1997;andin France (Marseilles andParis) in 1991 and1994. In the 2000s I gathered data from websites, primarily from online forum discourses of practitioners or sympathizers who commonly sell their services online and are trained by e-learning. Overall in my work I have directed the gaze on "ordinary," lay, common forms of qigong: those were cherished by most people and taught by ordinary masters or teachers. The life-world and life stories of these modest teachers enable the voices of lay practitioners to be heard. I collected a life story and in situ biography of Zhao lǎoshı 老師and shıfu 師父, an "ordinary" qıgong teacher and master mirroring my in-depth ethnographic work with him (Micollier 2013). Lǎoshı means "teacher" and shıfu "master." From his trainee's status and relation to Zhao, a student or a disciple, depending on the trainee's engagement in a specific and personalized training, Zhao is either a teacher or a master. More generally, in the qıgong world, the trainee's and trainer's status and denominations are defined from a relational standpoint much like the master-disciple nexus (shıfu-tudi, dizi) of knowledge transmission in the context of classical Chinese culture (Micollier 2004(Micollier , 2013)). To offer glimpses on the method as a process opening on new horizons, I recall below my actual work with Zhao lǎoshı and the transnational journey of his qıgong method. I accompanied him in his regular activities for almost a year in the early 1990s. In the morning, he would provide medical consultation at the Chinese medicine hospital in Guangzhou qıgong healing and teaching service (Guangzhou zhongyi xueyuan qıgong liaofa yanjiu shi 廣州 中醫氣功學院療法研究室); in the afternoon he would give private consultations and, in the evening, engage in qıgong courses within the framework of social and local organizations. He taught Fanteng gong 翻騰功, literally "training to increase and surpass human revitalizing qualities." This method aims to contribute to the treatment of cancer and HIV infection. It spread beyond China's borders in the 2000s and is practiced today at an international scale: one can easily search on the web to track it. This method is described in many European and Asian languages. In the late 2000s, it developed more specifically in Germany where it has many practitioners, as well as in Turkey. The practice is explained by masters who ensure its promotion and who often claim its development as they adapt to the contexts and create variants, as we have seen in the method of Zhao lǎoshı. Videos are available on YouTube and books on Google Books. Zhao's qıgong experiences and teaching involved both the transmission of inherited knowledge and innovation processes.

Framing a phenomenology of the body

In the context of qıgong culture and also mirroring the ethnographer's condition in the field, body languages, sensations, emotions, and feelings of a person in movement and within the world map produces a shared "life-world." Reflected in the writing or not, all these movements invite a reflexive journey. The ethnographer may approach it through bodily experience, participant observation and a sort of immersion, as far as possible, in the Chinese world past and present [START_REF] Micollier | Un aspect de la pluralité médicale en Chine populaire. Les pratiques de qıgong: dimension thérapeutique/dimension sociale[END_REF]. The physical and (psycho)physiological context is very important for the practice, as it co-creates a sensorial language moving in a designated actual and imagined space-time. Qıgong has the ability to fluidify its attributes and qualities according to practitioners' sensoriality and relationships, which develop from the immersive experience in these spaces. One can see, feel, and "inhabit" qı gong as a gymnastic, a therapy, and a collective or individual ritual, which has the power to move the human being toward well-being, health, and the development of the person, as well as in the domestic space, easily crossing and bridging generations. Phenomenological concern is implicit or explicit in any work about the body and personhood. Epistemological resonances involving phenomenologies vibrate in accordance with observed phenomena connected with knowledge, practice, ritual, and local healing, which produce movement in the body and the person, and thereby expose them. The interpretation of these phenomena is based on the epistemologies and ontologies of "others." Everyday lives are a chain of immediate experiences, which cannot be experienced but through the senses [START_REF] Merleau-Ponty | The Phenomenology of Perception[END_REF]. These experiences engage our embodied state in a processual way. Embodiment defined as "the bodily aspects of human beings and subjectivity" (Desjarlais and Throop 2011: 89) is considered as a paradigm for the anthropology of the body; the body being a living entity by and through which we experience the world [START_REF] Csordas | Embodiment as a Paradigm for Anthropology[END_REF]). Moving from the human body, entangled with the world body, to the social body, Csordas heuristically interlaces the notion of embodiment with the Bourdieusian habitus, addressing the issue of minoring the material and socioeconomic determinants of the human condition, and thereby replying to the most common claims against phenomenological approaches as a heuristic in social anthropology. In their programmatic mapping designed for further research in the anthropology of the body, Scheper-Hugues and [START_REF] Scheper-Hugues | The Mindful Body: A Prolegomenon to Future Work in Medical Anthropology[END_REF] identify the body as one and as multiple bodies, which can be unfolded into individual, social, and political bodies bounded together by emotions. Using "embodiment" as an actual and efficient process, [START_REF] Lock | Cultivating the Body: Anthropology and Epistemologies of Bodily Practice and Knowledge[END_REF] unbounds and weaves threads of prerogatives in a gradual move towards the erasing of limits of discourses. Discourses of and on the body are highlighted together with insights from the melody of biologies, cultures, and experiences intertwining (Lock 2001). The body is in perpetual becoming and constitutes a tangible interface between human and non-human entities, as well as time [START_REF] Latour | How to Talk about the Body? The Normative Dimension of Sciences Studies[END_REF]). Such theoretical orientation helps in understanding the crucial experience of the body: flows of entities, traveling in and out through an interstitial and porous envelope, which produce movements in and out of the body. This multifaceted body acts in return on these various entities creating a body in perpetual becoming while being moved through a perpetual process of co-constitution with the environment. Understanding bodily experiences as displaced and reframed by other entities, either human or non-human, is facilitated by Latour's conceptual lens, which closely bounds time and body. Finally, while adding to the body mapping, the quality of "agency" alive in all beings, relations between the human and non-human are better understood as interactions and interrelations rather than a mere co-presence in the world [START_REF] Descola | Beyond Nature and Culture[END_REF]. Mapping forms and paths of experiencing the world and "being toward the world," a number of anthropological studies have explicitly contributed to exploring phenomenologies in the context of culture. Here, I focus more specifically on a few significant works grounded in the context of East Asian cultures. Inspired by Husserl, Heidegger, and Merleau-Ponty while working in the context of Chinese culture, [START_REF] Ots | The Angry Liver, the Anxious Heart and the Melancholy Spleen. The Phenomenology of Perception in Chinese Culture[END_REF][START_REF] Ots | Phenomenology of the Body: The Subject-Object Problem in Psychosomatic Medicine and the Role of Traditional Medical Systems Herein[END_REF] favors the term "lived-body" [START_REF] Leder | Medicine and the Paradigms of Embodiment[END_REF]), rather than "embodiment" to properly understand "the body in human experience" (Merleau-Ponty 1962). However, the horizons of the "lived-body" and "embodiment" are not excluding each other in our phenomenological journey. Ots aims at raising awareness about the body as an inhabited, intelligent, and intentional entity. A modern cultural interpretation of the "natural" body blurred such knowledgeable views about the body (Heidegger 1979: 99-100). From premodern Europe, prior to the modern emergence of the body-mind dichotomy, a unique Scandinavian and Germanic term, leib, semantically gathers in one "life-person-body" (Ots 1990: 53, 55). In a work focusing on wind, life, and health, [START_REF] Low | Introduction[END_REF] explicitly referred to Merleau-Ponty's approach; Hsu captured the "wind," an historical etiological entity in the Chinese context, drawing on Ingold's views on environment [START_REF] Ingold | The Perception of the Environment: Essays on Livelihood, Dwelling and Skill[END_REF], himself genealogically inspired by the phenomenology of perception of [START_REF] Merleau-Ponty | The Phenomenology of Perception[END_REF].

At this juncture, I shall mention that while insisting in this article on the monist and holistic views in classical Chinese thought, the body-mind dichotomy is also assessed as an ancient notion in early China's historical sources [START_REF] Slingerland | Body and Mind in Early China: An Integrated Humanities-Science Approach[END_REF]. Therefore, this dichotomic view of the human being is not specific to European modern historical culture and the strong influence of Cartesian thought within it, as commonly claimed in the scholarly literature.

Bodily and sensory experi ences: qi cultivation (qigong), healing and development of the person

The term shentǐ (身體), as a noun used in common Chinese, means "person." In its verbal forms, it means either "to experience something personally" or "to put oneself in the position of someone else," focusing either on the experience of the person or the movement toward the other (Micollier 1999: 25). These meanings suggest to mobilize and cultivate empathy. The notion of the "body-person" [START_REF] Elvin | Tales of Sheng and Xin: Body-Person and Heart-Mind in China during the last 150 Years[END_REF]) evokes the body and the person in movement, although it remains difficult to find a lone word conveying both meanings in translation. In the following, I shall focus more specifically on the qualities and meanings of qı as crucial entities in the body and on their agentivity through their powerful transforming abilities. According to Zhao's teachings, three essential qualities of qı are connected with three body regions: the primordial qı (yuanqı 元氣) is used to heal the body parts situated below the vital center (dantian 丹田); the celestial qı (houqı 候氣, tianqı 天氣) targets the central part of the body at the level of the vital center; the authentic qı (zhengqı 正 氣) is efficacious in taking care of the uppermost part. Opening an ecological window, qı evocation reveals tight bounding and binding points with the environment and a movement involving sensoriality. Ancient uses and meanings of qı, including "breath, breathing, air, vapors, influences, emanations, clouds," situate them living in the worlds of physics, geography, and meteorology. Qı circulates within the body in correspondence with cosmic influences. Unschuld (1985: 72) translates them as "finest matter influences or emanations," taking into account the etymological and philological significance while encompassing the meaning of qı in the context of contemporary culture. Qı is a key determinant in the conceptualization of life and a basic concept in Chinese medicine theory. Current and common meanings of qı can be extrapolated as follows: (1) qı in connection with fate and so intrinsically a lifegiver (for instance yunqı 運氣, "qı in movement" usually translated "fate, fortune"; "you should accept the qı inside you, you should accept things as they are" (neizhong de qı lai, meiyǒu banfǎ yınggai shı yıng); (2) qı as vitality, force, dynamism; (3) qı as emotions; (4) qı as vibrations emanating from a person, or impression given by someone; this latter meaning being the most common (Micollier 1999: 24). Moreover qı is defined by qualities and localizations. In Chinese medicine basic theory, more than thirty qualities of qı can produce good or bad effects on the human body. Most have the ability to transform themselves into pathogenic agents affecting humans. Nevertheless, the benevolent quality of qı is also located in the human body and constitutes the basis for health, well-being, and longevity. The body has the potential to fight against pathogenic influences. Other constituents such as the essence (jıng 精) are defined as "treasures" (bǎo 寶). The interactions between qı and jıng weave a complex network of exchanges: according to the first part of the Internal Classic of the Yellow Emperor (Huangdi neijing suwen, Veith 1966), the fundamental classic of Chinese medicine, qı transforms itself into jıng and jıng feeds itself with qı . This reciprocal transformation 7of qı into jıng sheds light on their therapeutic complementarity. Shen embraces the organizational, transformable, and ever-lasting influence of individual impregnation. The body is conceived of as a reservoir of life and participates in the transformations of the world. Even though the life hosted in the body may generate disease, worries, and the exhaustion of the senses, the body nonetheless mediates the development and improvement of the person. The analogical horizon opens in the body and the world through the presence of multiple qı. The human and the world reciprocally reflect each other, with body parts mirroring cosmic entities (adapted from Chapter Seven of the Chinese classical book Huainanzi 1968 in [START_REF] Blanc | Huainanzi, Philosophical Synthesis in Early Han Thought[END_REF]: Qı is inscribed and lives in a geographical space: both the body and the world are situated in a spatial, temporal and relational continuum screened with analogical lenses.

The character qı 氣includes a pictogram showing "rising vapor" situated above of that of "rice" or "millet." The whole character means "vapors emanating from rice (or millet or food)" [START_REF] Engelhardt | Die klassische Tradition der Qi-Übungen[END_REF]. Another version of the character quoted in the etymological dictionary Shuowen [START_REF] Xu | [END_REF]) (approximately AD 100) combines the two components described above with a third one meaning "food" (shı 食), confirming the common historical reading "vapours emanating from the food." The pictogram qı is used in the second and third century literature in a broader range of meaning of "what fills in the body," "what life means," "breathing," "vapors," "clouds in the sky,"or even "wind" (Unschuld 1985: 72). From the Early Han dynasty (third century BC), a constituent made of "finest and dispersed vapors" is called qı and imagined as floating in the air and circulating in the body together with blood. These semantic uses resonate with a phenomenological reading through the evocation of perpetual flows of entities and between entities, and of the vaporous constituent disseminating in the world and impregnating it in a continual movement; so much so that a harmonious relation is bounded between the human and qı of all natural phenomena. Qı, feng 風(wind), and jıng 精(essence, sperm/vaginal secretions) have the ability to transform into one another. In a perpetual movement disseminated everywhere in the world, influences (qı) as constituents of life and the environment are also affluent inside organisms, moving in a fundamental circulation and in a porous world, where lines and limits are vanishing. Qı, as all entities, demonstrates agency.

From emotions in movement through qıgong experience and semantic fields of lay daily use of the term, qı acts as the dynamic agent demonstrating emotions and qualities of the person, as a spring for life, an agent of destiny (mıng 命), and a constituent of the person and of the world (Micollier 1999: 24). In Chinese medicine basic theory, nine qı are in an analogical relation with nine pathological states produced by excessive manifestations of the seven emotional states. As already mentioned, although qı may always transform itself in a pathological agent, it is almost never essentially pathogenic. However, the clinical reality of emotions reveals key divergences with the ancient theory of omnipresent correspondences (Ots 1990: 56).

Qıgong experiences are situated between consciousness and knowledge. They offer to the gaze flows of living qı in movement; these qı are influenced, acting, and agentive entities. While describing their experiences, qıgong practitioners clearly evoke actions and influences of qı, yın yang principles and the Five Phases (wǔxıng).

Experiencing is at the core of the ethnographic method involving participant observation and in-depth description dear to [START_REF] Geertz | The Interpretation of Cultures[END_REF]. The method in the world of Chinese cultural heritage refers to the Dao "path, way" of qı cultivation and the development of the person (xiushen), a work on the inner self, while gazing at remote horizons and aiming at the transformation and elevation of the person: qıgong leads to the development of the person with a gradual mastering of the art of qı. The ultimate experience aims at reaching a superior realm (gaojı jıngjie 高級境界) with "special, exceptional, extraordinary abilities" (teshu gongneng 特殊功能) such as clairvoyance, telepathic communication, receiving cosmic information, controlling energetic flows in levitating, miraculous curing powers, and so forth (Micollier 1995: 270). For instance, Zhao lǎoshı was teaching and curing through telepathy, and could stop the course of X and gamma rays. However of course, he also taught at the Chinese Medicine Institute and gave consultation and care in the service of qıgong research, treatment, and care in a more conventional way. In the qıgong world, the body of the practitioner is transfigured and movements open onto perpetual transformation. Qıgong is an array of sensorial participative experiences difficult to define, which cannot be captured with pre-constructed models. Its practice reveals a complex landscape of know-how and knowledge movements interlaced with movements of the world. Bodily, sensorial, and spiritually complete experience opening up horizons of the person in the world, qıgong is about inner life experience, sometimes an ecstatic experience connected with the charismatic experience of the master.

Qıgong states of mind (qıgong tai 氣功態) modify the consciousness of the body, a body inhabited and a habitant of this very body, a way of "being toward the world." Through body movements, one can perceive fluid links and interactions with the immediate surroundings. These processes ontologically illuminate a co-constitution body environment. Experiencing this in successive sequences is part of daily practice, producing gradual transformations of the person in movement. Fluid movements of expanding and constricting, and emotions connected with intermediary mental operations, are situated in between liberating and controlling them (Micollier 1999). Practitioners in movement toward a better being, in this situation patients in consultation, have indeed to let the flow of their emotions go beyond the barrier of an inhibiting behavior. Then the vistas of care, eventually of curing in a movement of reciprocal exchanges between the master and his beneficent qı and the qı of the patient, open up and expand.

In the healing movement, the world is located where the relationship of two persons (a therapeutic relationship) is born and grows. Engaged in this method of healing at a distance, two "body-persons," the patient and the healer, mediate the "body-world" and the world mediates exchanges between all beings, human and other than human, in a flow of reciprocal influences.

The master's beneficent qı and talent are transmitted by thought (to use the thought to project the talent and emit the qı, yong yınian fagong, faqı) operating in a precisely delimited spatial and temporal framework and received by the patient (shouqı). This reciprocal exchange and the flow and journey of qı constitute the matrix in this basic healing experience of qıgong. Qı has the "skill" (borrowed from Ingold 2000's perspective) to travel far away when correctly emitted and guided by a talented master. A localization to circumscribe a place (dıng difang), a direction (dıng fangxiang), or a time (dıng shıjian) needs to be arranged for facilitating interactions between the two persons. For instance, a telepathic technique works only when precise conditions are fulfilled: concentration is needed while conforming to the conditions of space and time previously delineated. This method is an individual and relational experience involving the sensibility previously developed. Practitioners use telepathy either in the context of a high-level training, aiming at the development of potentialities of the mind or in the context of an "at a distance" therapy. Patients come to see the master once, to start a therapy; later the follow-up is usually pursued at a distance. Health depends on the quality as well as on the intensity of qı sensations:

How are qı sensations produced? A person may experience tangible variations in daily life. You may perceive yourself either as bright and deep (shenmıng 深明) or as clumsy and stupid. While practicing qıgong, sensations producing conflicting feelings may be experienced.

Later you may hopefully experience fulfilling sensations again. (Zhao lǎoshı)

A healing session first aims at developing patient-practitioner sensibility to qı sensations. Qı emitting of the master-teacher is directly connected in a relational exchange to the reception of the qı by the patient. Any practitioner should be aware and expand the sensibility of following the nature of the body as a key principle of qı practice (Micollier 1995: 238). Although qıgong practice produces a constellation of qı sensations, these sensations are experienced and mediated differently. One may recommend to all to follow the nature of their body, the flow of life within. This sensibility should be developed with words and thought (yı): "Think about what I talk about. . .in one hand utter words; in the other hand use the thought." For instance, submitted to qı influence, most people react through emotional expression and body movements; they may laugh, weep, jump, move, in short let their body relax and express itself" (Micollier 1995: 239). Qı emitting moves flow, which are captured with the senses and thus embodied. At this juncture, I shall tentatively unravel threads of qıgong and Daoist experiences, and those of qıgong and Buddhist experiences, while simultaneously engaging with weaving a tight cloth between experience and consciousness.

Interlacing experience and consciousness: bounding qi cultivation, daoist and buddhist body and worlds

Daoist heritage resonates in qıgong experiences. Inner rituals reveal interlacement with Daoist experiences: the creation of a "qıgong space" and visualizing reminding of inner alchemy. A collective session where master Liao, another teacher-master whose experience intertwined with mine thanks to the trajectories of the biographical method, solicits movements of the body and the person opening in receiving the qı: "Let us relax. When you feel to scream, scream; when you feel to weep, weep; to dance, dance; to move, move (let your body, your emotions, your world live). Let you experience that" (Micollier 1999: 26). Practitioners in movement toward a better being, in this situation patients in consultation, have indeed to let the flow of their emotions go beyond the barrier of an inhibiting behavior. Then the vistas of care, eventually of curing in a movement of reciprocal exchanges between the master and his beneficent qı and the qı of the patient, open up and expand.

Qıgong forms in their diversity and among them the forms of medical qıgong, those that I studied more specifically, refer and borrow from Daoist cosmology, theory, and practice. This is also the case of Chinese medicine with which medical qıgong are intertwined. Located at the heart of Chinese culture, Daoism is rooted in an ancient form of shamanism, though not exclusively, and is born in China in contrast to Buddhism for instance, which made its journey from India (actual Nepal) to China in the first century A.C. As mentioned earlier, Daoism as a method and a theory reveals an ontology bounding tightly the body, the human being, and the world: a cosmology (myths of foundation), a method (aiming at knowing the intangible, incommensurable through the path "Dao" referring to Dao practice as a process of transformation), and a theory (a philosophy involving an analogical rationale). Chinese thought immerges into an analogical ontological world, and even more specifically a paradigmatic one of this type of ontology because it sharply unveils a crucial site of any analogical ontology, namely the difficulty of practically distinguishing among the components of existing entities, those connected with interiority from those connected with exteriority [START_REF] Descola | Beyond Nature and Culture[END_REF]. Bodily experience is an integral part of religious experience. In the context of Chinese culture, individual practices and the liturgy as a collective experience are connected with the regulation of the relation between the individual and their environment: visualizing techniques and inner rituals trace a continuum between the interior and the exterior. The body is then a protective envelope mediating perpetual exchanges between humans and their environment. In continuity with surroundings, the body immerges into the phenomenal reality. The lived body of the Daoist traces a blurred and extensible limit to the point of vanishing because the body has the ability to encompass but also to become the world itself; in a reciprocal movement, a dynamic process is connecting the human (the microcosm) and the environment, the universe, the world (macrocosm). Daoist thought is based on notions of relativity, impermanence, and the ability of transformation of any entity. Dynamic and vital relations between beings, human and other-than-human and their interrelations, correspondences weaving and networks intertwining grow through this relational "ever processing." Present in most world cultures, these views reflecting interlacing microcosm and macrocosm are developed and claimed in an extreme way through elaborate and systematic doctrinal tools involving both theory and practice. Body conception, perception and experience are the best example of these. Weavings and the threads which with they are made become more important than the beings and entities themselves.

The Daoist body is a pregnant woman's body, the all-encompassing body, the only one enabled to realize the transformation, the Dao 道ultimate work (Schipper 1982: 173). Roles and meanings of the pregnant woman's body are delineated in Daoist ritual practice. The human being is born as soon as he is conceived; the child's age is calculated from the fertilization process. Life inside the matrix resonates with the future life in the outside world. A temporal beat enables to determine the child's span of life in the world. The body of a pregnant woman, which is gradually ever expanding, constitutes a bodily model for the adept, who completely identifies with it to the extent of being able to experience the same metamorphosis through giving birth to the "immortal embryo" and making it grow inside the body person. A pregnant woman is a living being, no longer with borders: borders vanish in the expanding movement, enabling her a more acute sensibility while communicating ability. For the Daoist adept, a body endowed with a transformational ability opens onto the ultimate goal of involution to origin and of becoming "one" with the Dao. The transforming movement constitutes the core of Daoist practices; while the adept's body is dilating, it is projecting itself in the world and simultaneously incorporating world components. The metamorphosist's skill is the essential ability required for the creation of a "Daoist body" envisioned through the metaphor of the small child's "authentic Self." In the ritual experience, this ever-transforming body is a temple unveiling a superior and harmonious world inhabited with divinities.

The "Daoist body" is also a mystical body. The experience of a child's development shares similarities with that mystical experience through incorporating a "continuity between the inner world and the outer world, between the feeling of being one with the environment, which discovers itself being, for an essential part, another oneself" (Anzieu 1980: 160). From an enlightenment involving the senses, the mystic person returns to a primary state, which enables the transformation process. Furthermore, she lives a hard and painful regressive process: she is able to control it while simultaneously experiencing a primary state of non-integration and a limitless and original feeling of oneself [START_REF] Winnicott | Playing and Reality[END_REF]. [START_REF] Foucault | Les mots et les choses[END_REF] refers also to this notion of "aspects interlacing" when he evokes a set of rules regulating and orienting the "world prose." Last but not least, [START_REF] Levi-Strauss | The Savage Mind[END_REF] identifies a coherent rationale to the "savage mind" locating it at a strategic level of appropriating the natural world, which is approximately fitting to human perception and imagination.

In the Chinese thought, the "interlacing points" are the Five Phases (wǔxıng 五行), namely Wood, Fire, Earth, Metal, and Water imagined in perpetual transformation of one into another. Xıng means "go ahead, follow a path." The macrocosmic organism resonates with the human (microcosmic) organism: as the Dao without shape, which may be strong or weak, soft or hard, yin or yang (yın yang), dark or bright, the human on the path is changing, either expanding or concentrating, while his figure is undefined, ever evolving [START_REF] Seidel | La divinisation de Laozi dans le taoısme des Han[END_REF]). These resonances are crucial in Daoist meditation of internal organs, of spirits and deities inhabiting the body, which are visualized, and primordial forces are interiorized while one contemplates the exterior world through the visual sensorial organ, the eyes [START_REF] Robinet | Méditation taoıste[END_REF]. The human and the world are "organisms" from a physiological perspective like any cell or living being. From the first century A.C. Daoists developed the concept of body microcosm, which is also a bodypantheon. The deities living in the body are similar to the deities in the worldmacrocosm. The Daoist adept bounds body parts with regions of the universe through communicating with deities inside the body. In order to preserve qı, jıng (精), shen (神), the process of realizing the Dao consists of "nurturing the form" (yǎngxıng), "nurturing the life," (yǎngsheng), and cultivating the person (xiushen 修身) (Engelhardt 1987: 9). These experiences of the body, the person, and the world in perpetual movement nurture experience. The generic and simple technique of qıgong denominated "relaxing qıgong" (fangsong gong 放鬆功), which is a basic sequence in many qıgong forms, is based on the visualizing of various parts of the body, from the most internal (the essence jıng, namely sperm and vaginal secretions, and internal organs) to the most external sensorial elements (hair and skin). Visualizing internal organs is described as a fundamental technique of Daoist meditation in Chinese sources (Robinet 1979: 94-129). This very clear vision of the inner body evokes the "inner vision" of Daoist adepts. However, divinities living within the body vanished in modern qıgong experience (Micollier 2004). Zhao lǎoshı explicitly refers to the Daoist model of knowledge transmission through the development of a privileged master-disciple relation: My own master is a Daoist master of the Longmen group from the 19th generation. This Daoist master (daoshı 道士) is from the 24th generation. . .For instance, you and me, we are potential disciples and myself the master; between you all, no generation distinction whatever your age. In the case I am the first generation, you will be representative of the second one. In short, we shall all be affiliated to the Longmen branch. (Micollier 2013: 144) The school of the "Door of the Dragon" (Longmen pai 龍門派) is a branch of the Daoist school (Quanzhen dao 全真道). Inner rituals (neigong), which are at the core of the qıgong experience (described in [START_REF] Micollier | Un aspect de la pluralité médicale en Chine populaire. Les pratiques de qıgong: dimension thérapeutique/dimension sociale[END_REF]Micollier , 2004)), echo strongly with the experience of inner alchemy (neidan). This form of Daoist meditation, dear to the Quanzhen school, includes the visualization of a whole range of divinities living within the body, which in the end comprehend a whole pantheon [START_REF] Robinet | Méditation taoıste[END_REF](Robinet , 1991)).

The ethnographic experience enables one to see the weaving of tight threads between qıgong and Daoism within a movement of theoretical, sensorial, and experiential interlacing. The world and its cosmological mapping, the body and person's experiences, the collective experience, the history and knowledge path in qıgong located between innovations and heritage transmission, and the religious affiliations of master and practitioners all contribute to this weaving process. This spatial and temporal movement gives birth to shapes with uncertain and ephemeral outlines, and traces lines of encounters and lines of flight in between these actual experiences of qı's cultivation. Qıgong experiences are also deeply connected with Buddhist lore: depending on specific qıgong forms and masters' teachings, variations in the form, the choreography of movements, interactions, relations, and ritual processes together resonate with Buddhist experiences. For instance, practitioners transport themselves in lotus flowers'space and practice Oneness (lianhua taishang lianyı 蓮花台上練一; Micollier 1995: 210-215) where they develop "knowledge produced by the thought in action" (yıshı zhıshi 意識知識). In his own training, teaching or healing, Zhao lǎoshı chants the mantra Om mani padme om in Tibetan or in Chinese (Hong mami bei mi hong).

From the discourses of practitioners on some modified or liminal states of consciousness they had experienced, and also observed situations, I described experiences recalling "near-death experiences" through various qualities of "qıgong state, attitude" (qıgong tai 氣功態) and the intensity of this transformation of overall mental state (Micollier 1999). Sensorial and perceptual experiences of practitioners evoke those of people living mental transformations, experiencing expanded or modified states of consciousness (Micollier 1999;[START_REF] Chen | Breathing Spaces. Qıgong, Psychiatry and Healing in China[END_REF]) and near-death experiences in religious experiences [START_REF] Becker | The Centrality of Near-Death Experiences in Chinese Pure Land Buddhism. Anabiosis[END_REF] or in coma-related neurological experiences. [START_REF] Becker | The Centrality of Near-Death Experiences in Chinese Pure Land Buddhism. Anabiosis[END_REF] philosophical study highlights the centrality of near-death experiences in the practice of Pure Land Buddhism (Jıngtǔ zong).

Discussing the how and why of human experience and interestingly taking it as entry and exit points, phenomenology and Buddhism deeply interrogate the human condition; they both aim at elucidating similar epistemological issues, namely perceptions, sensations, cognition, noetic construction, embodiment conditioning, limitations, and going beyond embodied paths to comprehend the world. Their shared objective is to solve the most crucial human dilemmas and issues through a methodic investigation of the means of knowledge [START_REF] Lusthaus | Buddhist Phenomenology: A Philosophical Investigation of Yogacara. Buddhism and the Ch'eng Wei-shih Lun[END_REF].

Conclusion

Phenomenological engagements show affinities with East Asian philosophies [START_REF] Depraz | On Becoming Aware: A Pragmatics of Experiencing[END_REF]. From theory to method, applying phenomenology, "seeing" experience, and "becoming aware" [START_REF] Depraz | On Becoming Aware: A Pragmatics of Experiencing[END_REF] resonate with qi cultivation, Buddhist and Daoist experiences.

Undoubtedly, the qıgong world opens up the body person, the "life world," social and politico-religious reality, and religious experiences. Through their immediate lived experiences, qıgong practitioners develop sensibility (mǐngǎn 敏感) to qıs (qıgǎn氣感): these qıs are living and are active entities in bodies and persons in movement, and reciprocally humans have transforming power upon them. Body experience involving all the senses, breathing, emotions, and feelings sheds light on a body co-constituted by, and inhabiting, the surrounding world. These sensorial experiences are situated in both a material and a social world. Inspired by Merleau-Ponty's phenomenology of perception and Latour's proposal on the body, to closely bind it to time, my article sheds light on qıgong experience involving immediate sensorial perception, an experience of embodiment opening onto other horizons. The qıgong world immerges into the life world of persons through a fundamental sensory nonverbal experience, offering to the gaze movements, sounds, and gestures, with some such gathered into martial or performing arts forms. These choreographic sets sketch an aesthetics and a poetic of the body, reflecting emotions, feelings, and relations between persons within an "inhabited" space. Practitioner-dancers move through a material and mental space delineated by their master. First therapeutic, rather than aesthetic bodily expression, this inhabited space discretely depicts the space of Daoist ritual even though not perceived and thought as such by the "dancers." These bodily experiences unveil a poetic of the body in movement and transformation, animating people's daily life. As I have hopefully demonstrated in this article, these are woven together with phenomenologically interlaced threads of affects, sensations, and emotions, constituting a heavy share in experience. This article tentatively unravels the threads of an anthropology of the body feeding on phenomenological air coming both from Europe and East Asia, more specifically the Chinese world. This anthropological engagement resonates at both the theoretical and the methodological, more precisely the empirical level. Bodies in movement shed light on a choreography, which is an invitation to comprehend how the interplay between anthropology and phenomenology can offer critical and innovative views. Throughout our journey in the qıgong world and religious experiences, the interlacing of experience and consciousness immerges in the life world of the individual and human groups through a relational analytical lens and along the lines of a phenomenology of perception.

Table 1 .

 1 -The body and the world: analogical correspondences

	BODY	WORLD
	Head	Sky
	Feet	Earth
	Human being (four limbs)	One year (4x3 months)
	366 articulations	366 days
	Eyes + ears	Sun + moon
	Blood + qi	Wind + rain
	9 Body orifices	9 Doors of the earth, 9 Celestial strata
	5 Receptacles	5 Phases of transformation


Dr Ludovic Fournel
email: ludovic.fournel@aphp.fr

Zherui Wu

Nicolas Stadler

Diane Damotte

Filippo Lococo

Geoffroy Boulle

Evelyne Ségal-Bendirdjian

Antonio Bobbio

Philippe Icard

Jean Trédaniel

Marco Alifano

Patricia Forgez

Cisplatin increases PD-L1 expression and optimizes immune check-point blockade in non-small cell lung cancer

Keywords: Immune check-point inhibitors, cisplatin, PD-L1, lung cancer, neoadjuvant treatment

à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

List of abbreviations

The survival of patients with metastatic lung cancer has significantly improved with platinumbased treatments and, more recently, with targeted therapies and immunotherapies. Despite therapeutic advances, lung cancer remains the world-leading cause of cancer-related death (approximately 2 million per year), due to innate or acquired tumor resistance to treatments [START_REF] Torre | Lung Cancer Statistics[END_REF]. Identifying theranostic biomarkers to target the right population remains a major objective in the clinical management of this disease. Indeed, programmed cell death 1 (PD-1) and ligand (PD-L1) check-point blockade allows durable disease control and increased survival rates as compared to conventional chemotherapy [START_REF] Pawel | Long-term survival in patients with advanced non-small-cell lung cancer treated with atezolizumab versus docetaxel: Results from the randomised phase III OAK study[END_REF][START_REF] Herbst | Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial[END_REF][START_REF] Reck | KEYNOTE-024 Investigators, Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer[END_REF]. However, this advantage occurs in only a subset of metastatic non-small cell lung carcinoma (NSCLC) patients, as those exhibiting more than 50% PD-L1-stained tumor cells [START_REF] Pawel | Long-term survival in patients with advanced non-small-cell lung cancer treated with atezolizumab versus docetaxel: Results from the randomised phase III OAK study[END_REF][START_REF] Reck | Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater[END_REF]. Considering the widespread use of immune check-points inhibitors (ICIs) in different settings of the NSCLC multimodal treatment, a pronounced interest has been shown for PD-L1 expression and its regulation [START_REF] Vareki | Biomarkers of response to PD-1/PD-L1 inhibition[END_REF][START_REF] Dong | Potential biomarker for checkpoint blockade immunotherapy and treatment strategy[END_REF]. Several studies evaluated the impact of systemic treatments in tumor microenvironment, most notably with platinum-salts, and the ability of chemotherapy to modulate tumor immunogenicity and more generally to influence protagonists of the adaptive immunity [START_REF] Shin | Effect of Platinum-Based Chemotherapy on PD-L1 Expression on Tumor Cells in Non-small Cell Lung Cancer[END_REF][START_REF] Zhang | Upregulation of programmed cell death ligand 1 promotes resistance response in non-small-cell lung cancer patients treated with neo-adjuvant chemotherapy[END_REF].

Even though the implicated mechanisms remain undetermined, some authors proposed a transcriptional up-regulation of PD-L1 gene by oncogenic signaling pathways such as mTOR/PI3K/AKT [START_REF] Zerdes | Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations[END_REF][START_REF] Lastwika | Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer[END_REF]. This represented a rationale for clinically testing combination treatments associating chemotherapy to anti-PD-1/PD-L1 [START_REF] Paz-Ares | KEYNOTE-407 Investigators, Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer[END_REF][START_REF] Gandhi | KEYNOTE-189 Investigators, Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer[END_REF][START_REF] Liu | Long-term survival follow-up of atezolizumab in combination with platinum-based doublet chemotherapy in patients with advanced non-small-cell lung cancer[END_REF][START_REF] Antonia | PACIFIC Investigators, Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer[END_REF]. In the present study, we evaluated the impact of cisplatin on PD-L1 expression in patients receiving cisplatin-based neoadjuvant chemotherapy (NAC) and in preclinical models of lung cancers, along with combined therapies involving ICIs.

2.Materials and methods

Patients and surgical specimens

We retrospectively reviewed a cohort of 122 patients operated in a single-center of thoracic surgery between 2000 and 2007, for curative-intent resection of locally-advanced lungcarcinoma after NAC which allowed partial response (PR) or stable disease (SD), at computed-tomography evaluation [START_REF] Eisenhauer | New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)[END_REF]. All cases were preliminarily discussed by a multidisciplinary board. In 39 out of 122 cases, paraffin embedded blocks of metastatic ipsilateral mediastinal lymph-nodes, obtained at initial staging by mediastinoscopy or anterior mediastinotomy, were available for performing matched analysis with post-chemotherapy tumor specimens, subsequently allowing comparative immunochemistry (IHC) assessment of PD-L1 expression. To note, molecular analyses such as EGFR or K-ras mutations and ALK-ROS1 rearrangements testing, were not performed, at that time. Epidemiologic data, clinical and pathological responses to chemotherapy (expressed as percentage of necrosis, fibrosis to viable tumor cells) were collected and analyzed. "Viability" was defined by the presence of tumor cells exhibiting distinct nuclear chromatin, and intact nuclear or cytoplasmic membrane, and the absence of sign of necrosis (i.e. karyorrhexis, karyolysis, and pyknosis).

In addition, we evaluated the PD-L1 status in a second cohort of 20 patients who underwent up-front surgical resection of NSCLC with postoperative pathological mediastinal lymphnode assessment showing minimal pN2 disease. As these patients did not receive any NAC, the comparative evaluation of PD-L1 status between invaded lymph nodes and pulmonary tissues was used as "control" group.

Informed consent was obtained from all patients or relatives (in case of deceased patients).

The protocol was approved by the local ethics committee (CPP Ile de France II, n°2008-133 and 2012 06-12) in agreement with French law and declaration of Helsinki.

Immunohistochemistry staining and evaluation

For each tumor, we performed PD-L1 immunostaining on fresh-cut slides from representative blocks using an anti-PD-L1 antibody (E1L3N, Cell signaling) on Bond automat (Leica) as previously described and validated by the PATTERN French thoracic pathologists group [START_REF] Adam | Multicenter harmonization study for PD-L1 IHC testing in non-small-cell lung cancer[END_REF].

Staining was double blinded analyzed by at least one expert pathologist. PD-L1 staining evaluation on tumor cells was based on previously published scores [START_REF] Herbst | Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients[END_REF]. Briefly, tumor cell PD-L1 staining was scored as the percentage of positive cells. The variable ΔPD-L1 was calculated as the difference of the percentage of tumor cells labeled for PD-L1, before and after treatment. Patients who exhibited a switch of PD-L1 labeling from <50% to ≥50% tumor cells were categorized as ΔPD-L150 positive. The immune cells scoring for PD-L1 staining was attributed as follows: score 0: no immune cells positive for PD-L1; score 1: 1 to 10% of the tumor surface occupied with PD-L1+ immune cells; score 2: more than 10% of the tumor surface occupied with PD-L1+ immune cells. Alveolar macrophages were not counted within the immune cells positive for PD-L1.

Staining of CD8 lymphocytes was performed using anti-CD8 antibodies (SP16, Spring Bio).

After incubation sections were scanned using Nanozoomer, and count of CD8+ cells performed with Halo ® software to calculate the cell density expressed as number of stained cells/mm 2 . A secondary analysis was then performed in the tumor zone predefined manually to evaluate the density of intra-tumor T-lymphocytes.

Cell lines, culture and reagents

The human lung cancer cell lines A549 (CCL-185™), and murine cells from Lewis lung carcinoma model LLC1 (CRL-1642™) were purchased at ATCC®. LNM-R was subcloned from LNM-35 as described previously [START_REF] Alifano | Neurotensin receptor 1 determines the outcome of non-small cell lung cancer[END_REF]. All cells were grown in DMEM (Gibco®) supplemented with 10% fetal bovine serum (FBS) (Gibco®) and 2 mM glutamine, at 37 °C, in a humidified atmosphere of 5% CO2 [START_REF] Younes | Neurotensin (NTS) and its receptor (NTSR1) causes EGFR, HER2 and HER3 over-expression and their autocrine/paracrine activation in lung tumors, confirming responsiveness to erlotinib[END_REF]. For in-vitro experiments, cells were grown until 80% confluence and then exposed to different treatments in media supplemented with 1% FBS. The AKT-inhibitor MK2206 was purchased from Selleckchem®.

Quantitative RT-PCR, SDS-Page, Western-blotting and immunocytochemistry

assays were performed as previously described [START_REF] Wu | Modulation of lung cancer cell plasticity and heterogeneity with the restoration of cisplatin sensitivity by neurotensin antibody[END_REF]. See details in supplementary methods.

Tumor xenografts

Four-week-old male athymic NMRI-Foxn1 nu/nu mice (Janvier™) and C57BL/6j (Janvier™) were used to generate experimental tumors by grafting human lung cancer cell lines (A549, or LNM-R), or mouse lung carcinoma cell line (LLC1), respectively. Mice were injected in the flanks at single or multiple injections, according to the experiment, with 10 6 LNM-R cells, 5 x 10 6 A549 cells, or 5 x 10 5 LLC1 cells. When tumors reached a volume of 90-100 mm3 (tumor volumes were calculated using the formula: (L x W 2 )/2), animals were randomized in the 5 following treatment groups and received retro-orbital injections of: cisplatin (cisdiamminedichloroplatinum(II): CDDP), vehicle (PBS), anti-PD-L1 (Bio X cell®, 10mg/kg), murine total-IgGs, or the combination CDDP and anti-PD-L1. The antibodies were injected at the dose of 10mg/kg at day 1 and 5. The CDDP was injected at the dose of (1mg/kg) at day 1, 3, 5, 8, and 10. Basing on preliminary experiments, the posology of cisplatin was chosen to remain with a sub-toxic dose (LD50 for cisplatin-injected i.p in mice of 12 mg/kg).

All procedures were performed in accordance with the "Guide of the Care and Use of Laboratory Animals". An institutional review board approval was obtained by «Le Comité d'Ethique en l'Expérimentation Animale Charles Darwin # B751201».

Statistics

Descriptive data were expressed as frequencies for qualitative variables and mean (±SD) or median for continuous variables according to the observed distribution. In columns, curves, or ΔPD-L1 statistics, data were expressed as mean (±SEM). Categorical data were compared using Chi 2 , or Mac-Nemar test, as appropriate. Continuous and normally distributed variable resulting from the analysis of matched tissues were performed using paired student t-test.

Comparisons between groups were performed using two-way ANOVA. Statistical analyses were performed using GraphPad Prism (GraphPad Software, Inc. La Jolla, USA).

Results

PD-L1 expression is not different in lung primary tumor and associated metastatic mediastinal lymph-nodes.

We analyzed PD-L1 expression from both primary lung cancer and associated metastatic lymph nodes in 20 patients with N2 disease who did not receive any induction therapy (minimal N2). As shown in figure 1A, no significant difference was observed between the two sites (p=0.62). Thus expression of PD-L1 at metastatic nodal locations can be considered as representative of those in the primary tumor allowing comparative analysis of PD-L1 expression in lymph-nodes cancer cells (baseline) and post-NAC resected lung tumor specimen from the same patient. Respective data were used for calculating ΔPD-L1.

Cisplatin-based NAC induces PD-L1 expression by tumor and immune cells in resected specimens of human NSCLC.

Thirty-nine patients with available pre-and post-chemotherapy matched tumor tissues were identified. There were 29 (74.4%) men and 10 (25.6%) women, with mean age 56.5 (±8.1) years. Most of patients were smokers (76.9%) with a mean tobacco consumption of 37.1 (±6.2) pack-years. Chronic obstructive pulmonary disease (COPD) patients represented 51.3% of the whole cohort. Induction chemotherapy consisted in administrations of a doublet including cisplatin which allowed PR or SD in 15 (38.5%) and 24 (61.5%) patients, respectively.

The pathological analysis of resected specimens revealed that tumors were predominantly adenocarcinomas) and that mean rates of histologic changes were distributed as follows: necrosis 16.1 (±20.3) %, fibrosis 48.2 (±27.7) %, and viable tumor cells 35.7 (±23.0) % (table 1. The IHC results of PD-L1 staining showed a higher percentage of labeled tumor cells after NAC than baseline (26% versus 11%, respectively, p=0.017), suggesting an inducing effect of cisplatin on PD-L1 expression (figure 1B,C). Interestingly, ΔPD-L1 was positive, zero or negative in 22 (56.4%), 8 (20.5%) and 9 (23.1%) of the cases, respectively (figure 1D).

Among the 22 ΔPD-L1 positive patients, 9 (23.1% overall) exhibited a switch of PD-L1 labeling from <50% to ≥ 50% and were categorized as ΔPD-L150 positive. Analyzing the possible associations between PD-L1 expression and pathological changes after NAC, we noted that the subgroup exhibiting < 5% of PD-L1 positive tumor cells in lymph-nodes (pretreatment) showed significantly higher rate of fibrosis (p=0.034) and a trend towards lower rate of viable tumor cells (p=0.101) after NAC. Inversely, more than 50% of PD-L1 positive tumor cells in the lung primary (post-treatment) was significantly associated to a lower rate of fibrosis (p=0.030), but a higher rate of necrosis (p=0.011) after NAC. Furthermore, we observed that the rate of specimens with more than 50% viable tumor cells was significantly higher in the subgroup of ΔPD-L150 positive cases versus ΔPD-L150 negative ones (p=0.019) (table 2). PD-L1 staining of immune cells in the microenvironment was also evaluated and compared between matched pre-and post-chemotherapy tissues. The percentage of tumors exhibiting a PD-L1 immune-score >1 was significantly higher in the post-treatment group (25.6% versus 10.3%, p=0.001), suggesting an up-regulation of PD-L1 by cisplatin in immune cells (figure 1E). The rate of viable tumor cells shows a pronounced trend towards an increase in the group of patients with positive immune-score variation (43.6% versus 31.8% mean rate of viable tumor cells in positive ΔPD-L1 immune-score versus others, p=0.11).

Concerning CD8+ staining in matched samples, the mean number of CD8+ lymphocytes in the tumor area did not significantly change after induction therapy (p=0.59, figure 1F). In addition, there was no significant association between variations of PD-L1 in tumor cells and corresponding number of CD8+ lymphocytes (p=0.92).

Cisplatin increases PD-L1 expression in experimental tumors.

To confirm our clinical results and better investigate the influence of cisplatin on PD-L1 regulation, we established experimental tumors using the syngeneic model of Lewis lung carcinoma. First, we confirmed that LLC1 cells express PD-L1, as a strong band for PD-L1 transcript was observed by RT-PCR (figure 2A). We then analyzed the level of PD-L1 protein content in the LLC1 tumors before or after cisplatin treatment for 24 hours. An example of a western blot is shown in figure 2B. The semi-quantitative estimation demonstrated a significant increase of PD-L1 protein in the tumor after treatment (p=0.02, figure 2C).

To eliminate the influence of the immune component in this regulation, especially Tlymphocytes, we evaluated PD-L1 expression in a model of athymic nude mice bearing tumors from human lung adenocarcinoma cell line (A549). Comparative analysis of tumor samples showed a significant increase of PD-L1 mRNA level after treatment with 24-hour cisplatin (p=0.03, figure 2D). In control groups receiving injection of PBS alone, PD-L1 transcript levels were not modified (p=0.53).

Cisplatin rapidly increases PD-L1 expression in a dose-dependent manner, via AKT activation

To further explore the modality of actions of cisplatin on tumor cells, we incubated different human and murine lung carcinoma cell-lines, expressing PD-L1 at baseline, with increasing concentrations of cisplatin. After treatment, the rates of PD-L1 mRNA were increased in both human and murine cell lines, by 1.5 to 7.5 folds as compared to control groups (figure 3A-C).

In human LNM-R cells, in which we found an IC50 % of 12±3.1 µM cisplatin, the enhancement of PD-L1 expression was observed at a very low dose, then dose escalation of cisplatin was positively correlated to PD-L1 mRNA levels and reached a plateau around 8µM (figure 3A). This increase of PD-L1 transcript was also observed in others cell lines (figure 3B andC). Concomitantly, the PD-L1 protein levels were also increased in the three cell lines, as compared to respective controls (figure 3D). As PD-L1 is a trans-membranous protein, we subsequently performed an immunocytochemistry analysis showing cisplatininduced enhanced labeling of the cytoplasmic membrane as compared to control (figure 3E). Furthermore, we evaluated the role of the PI3K/AKT pathway in PD-L1 up-regulation by cisplatin. LLC1 cells were treated for 24 hours with 8µM of cisplatin plus or without MK2206, an AKT blocker, or DMSO. The RNA quantification revealed that cisplatininduced PD-L1 up-regulation was significantly counteracted by MK2206 (figure 3F). This effect was confirmed at the protein level with western-blot analyses showing a significantly lower PD-L1 expression in the group of cells incubated with combined cisplatin and MK2206 as compared to cisplatin and control (figure 3G). Overall, these results suggest that PD-L1 upregulation by cisplatin could involve the PI3K/AKT signaling pathway.

The combined treatment associating cisplatin and anti-PD-L1 improves therapeutic response compared to single agent regimens.

As PD-L1 expression was increased after cisplatin exposure, we addressed the question of a potential improvement of tumor response with the combined treatment associating cisplatin and anti-PD-L1 antibodies, as compared to single agent regimen. As previously described, we performed syngeneic grafts of LLC1 tumors to C57BL/6j mice. The treatment began when the tumor burden reached 90 to 100 mm 3 , two weeks after cell injection. The tumor growth was rapid as the control group reached 3000 mm3 after 15 days. Consequently, in accordance with ethical guidelines, we terminated the experiment. The tumor growth rate was not significantly different between the control, the isotope IgG, the PD-L1, and the cisplatin groups. In contrast, the tumor volume was reduced by 47% in mice treated with the combined treatment as compared to control (1530 ± 147 vs 2879 ± 400 mm 3 ) (figure 4A). Individual responses, shown in figure 4B, revealed that in control, and IgG groups, the tumor growth rate was dispersed among animals, and more homogenous in the single agent regimen groups except some mice exhibiting high tumor progression. Tumor response in the group receiving combined cisplatin and anti-PD-L1 was also homogeneous, all 10 tumor-bearing mice showed almost similar tumor growth delay (figure 4B).

Discussion:

In the present study, we showed that cisplatin up-regulates PD-L1 with consistent results obtained in several cellular models and experimental tumors, as well as in series of patients.

In addition, the clinical and pathological results observed in the NAC cohort, our preclinical experiments revealed an early induction of PD-L1 by cisplatin associated with significant biological effect. The paired analysis of human tumor samples revealed an increase of PD-L1 expression several weeks following cisplatin administration, which suggests prolonged upregulation in tumor cells. These results is in contrast to previous observations in head and neck squamous-cell carcinoma, suggesting that cisplatin-induced PD-L1 up-regulation might not be sustainable over time [START_REF] Tran | Cisplatin Alters Antitumor Immunity and Synergizes with PD-1/PD-L1 Inhibition in Head and Neck Squamous Cell Carcinoma[END_REF]. An up-regulation of PD-L1 by cisplatin, being both early and sustainable, would have a major impact in the design of combined systemic therapies protocols including cisplatin and ICIs. Similarly, some authors previously demonstrated that platinum-based NAC can induce PD-L1 expression in various cancers which could favor the results of consecutive ICIs treatment [START_REF] Tran | Cisplatin Alters Antitumor Immunity and Synergizes with PD-1/PD-L1 Inhibition in Head and Neck Squamous Cell Carcinoma[END_REF][START_REF] Grabosch | Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles[END_REF][START_REF] Ng | Chemotherapeutic Treatments Increase PD-L1 Expression in Esophageal Squamous Cell Carcinoma through EGFR/ERK Activation[END_REF][START_REF] Mesnage | Neoadjuvant chemotherapy (NACT) increases immune infiltration and programmed death-ligand 1 (PD-L1) expression in epithelial ovarian cancer (EOC)[END_REF]. Even though true benefit of such therapeutic association probably needs to be overbalanced with the theoretical negative impact of NAC on immune cells, our team previously demonstrated that platinum based chemotherapy does not affect the immune contexture of post-induction NSCLC [START_REF] Remark | Immune contexture and histological response after neoadjuvant chemotherapy predict clinical outcome of lung cancer patients[END_REF]. In this study, we chose to mimic the clinical context by using a subtoxic dose of cisplatin, and obtained an improved tumor response combining cisplatin to anti-PD-L1 antibodies compared to single agent regimen. Thus we can emphasize that administration of cisplatin can up-regulate PD-L1 while not significantly impairing anti-cancer immunity.

The independent role of cisplatin on PD-L1 expression in NAC patients could be challenged as cisplatin was combined to other chemotherapeutic agents. However, we did not find any statistical association between ΔPD-L1 and type of doublet. In addition, several retrospective studies analyzing the effect of cisplatin-based NAC in other neoplasms than NSCLC found similar results concerning its influence on PD-L1 expression whereas regimen protocols generally involve different associations than in lung cancer [START_REF] Grabosch | Cisplatin-induced immune modulation in ovarian cancer mouse models with distinct inflammation profiles[END_REF][START_REF] Ng | Chemotherapeutic Treatments Increase PD-L1 Expression in Esophageal Squamous Cell Carcinoma through EGFR/ERK Activation[END_REF]. Thus it can be concluded that cisplatin could play a significant role in PD-L1 expression by tumor cells.

The methodology consisting in analyzing ΔPD-L1 after NAC by comparing IHC results in metastatic and primary tissues seems relevant and advantageous. Indeed, our results on chemo-naive minimal-N2 patients, showed no significant difference between PD-L1 staining in lung tumor and invaded mediastinal lymph nodes. Although relying on the analysis of "only" 20 patients, because of the rarity of minimal N2 condition, this result suggests that PD-L1 labeling in lymph-nodes is representative of those from primary lung tumors. Despite the potential for slightly different clinical and biological entities, other authors have corroborated findings and reported similar or higher PD-L1 expression in tumor cells of metastatic sites as compared to primary sites [START_REF] Liu | Heterogeneity of PD-L1 Expression Among the Different Histological Components and Metastatic Lymph Nodes in Patients With Resected Lung Adenosquamous Carcinoma[END_REF][START_REF] Uruga | Programmed Cell Death Ligand (PD-L1) Expression in Stage II and III Lung Adenocarcinomas and Nodal Metastases[END_REF].

Our results outline a strong association between changes in PD-L1 expression by tumor cells and pathological features of tumors after NAC, in line with similar findings [START_REF] Zhang | Upregulation of programmed cell death ligand 1 promotes resistance response in non-small-cell lung cancer patients treated with neo-adjuvant chemotherapy[END_REF]. It has been reported that high PD-L1 expression in tumors was associated with resistance to cisplatin, and also that ΔPD-L1 after induction therapy might reflect chemosensitivity, with low or no ΔPD-L1 positivity in those patients responding to cisplatin [START_REF] Zhang | Upregulation of programmed cell death ligand 1 promotes resistance response in non-small-cell lung cancer patients treated with neo-adjuvant chemotherapy[END_REF][START_REF] Lee | PD-L1 polymorphism can predict clinical outcomes of non-small cell lung cancer patients treated with first-line paclitaxel-cisplatin chemotherapy[END_REF]. Out results concur with this hypothesis based on the finding that ΔPD-L150 positive patients exhibit worse pathologic criteria of response to NAC. To explain this correlation, we may hypothesize that neoadjuvant treatment "selected" the subset of tumor cells resistant to cisplatin and, thus, still viable after induction therapy, these resistant clones exhibiting higher PD-L1 expression. Moreover, this latter observation possibly links to some mechanisms involved in PD-L1 up-regulation which are currently under investigation. Indeed, the regulation of this protein is very complex and involves many transcriptional, post-transcriptional and post-translational actions, the clarification of which would be best suited for individual studies [START_REF] Zerdes | Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations[END_REF]. Our preliminary mechanistic exploration focused on a relatively ubiquitous oncogenic signaling pathway but specifically reported as up-regulating PD-L1, and known to sustain survival and resistance to cisplatin-induced apoptosis in cancer cells: PI3K/AKT [START_REF] Lastwika | Control of PD-L1 Expression by Oncogenic Activation of the AKT-mTOR Pathway in Non-Small Cell Lung Cancer[END_REF][START_REF] Mittendorf | PD-L1 expression in triple-negative breast cancer[END_REF][START_REF] Sarris | The Biological Role of PI3K Pathway in Lung Cancer[END_REF]. The present study supports these observations showing that inhibition of PI3K/AKT pathway resulted in a significant reduction of PD-L1 expression in tumor cells exposed to cisplatin.

Increased PD-L1 expression in immune cells of the microenvironment after NAC represents another important result. Indeed, sustained stimulation of the PD-1/PD-L1 axis may alter antitumor activity as it has been shown that high proportions of PD-L1+ regulatory and PD-1+CD8+ T-lymphocytes in the stroma of NSCLCs were significantly associated with good response to ICIs [START_REF] Wu | Stromal PD-L1-Positive Regulatory T cells and PD-1-Positive CD8-Positive T cells Define the Response of Different Subsets of Non-Small Cell Lung Cancer to PD-1/PD-L1 Blockade Immunotherapy[END_REF]. In further studies, it would be interesting to explore the impact of treatments combining cisplatin-based chemotherapy and ICIs, in a concomitant or sequential manner, on anti-tumor immunity. Interestingly, the influence of number and function of immune cells of the microenvironment on the outcome of combined ICIs and NAC should be further investigated.

Limitations:

All PD-L1 IHC evaluations relied on a retrospective cohort including a limited number of operated patients harboring heterogeneous clinical and pathological characteristics. Molecular analyses were not routinely performed at time of initial management and could not be performed for the current study. Thus, we could not analyze the impact of tumor mutational burden on ΔPD-L1 and its microenvironment. In addition, the reliability of pre-and postcisplatin matched tumor biopsies analyses could be challenged by the likely heterogeneity of PD-L1 expression within the whole tumor area, encouraging a cautious interpretation of observed differences [START_REF] Ilie | Comparative study of the PD-L1 status between surgically resected specimens and matched biopsies of NSCLC patients reveal major discordances: a potential issue for anti-PD-L1 therapeutic strategies[END_REF][START_REF] Munari | PD-L1 Expression Heterogeneity in Non-Small Cell Lung Cancer: Defining Criteria for Harmonization between Biopsy Specimens and Whole Sections[END_REF]. This methodological limitation also occurs in our mice experiments which, moreover, harbor drawbacks for mimicking "normal" tumor stroma and microenvironment due to the heterotopic location and the rapid growth of injected pulmonary tumors [START_REF] Zitvogel | Mouse models in oncoimmunology[END_REF].

Conclusion:

In conclusion, cisplatin enhanced PD-L1 expression in both preclinical models and cohorts of patients with NSCLC. The results suggested reproducible, persistent, and a significant inducing impact on tumor cells. This study will hopefully provide a solid and reliable basis for further explorations, as well as reinforcing the rationale for several ongoing clinical trials testing combination therapies including PD-L1 and cytotoxic drugs like cisplatin. At the time of protocols combining chemo and/or radiotherapy with ICIs, it also raises the question of the relevance of performing sequential reevaluation of PD-L1 status to select the ideal subset of patients.

Acknowledgements

We thank Dr Neil Insdorf for his kind help in editing the manuscript. We thank Tatiana Ledent (animal facility, Saint-Antoine Hospital, Paris, France) and staff of the microscopy platform SCM (Service Commun de Microscopie, Faculté des Sciences Fondamentales et Biomédicales, Paris, France)". We also thank Dr Cecilia Mengoli for her help in immunochemistry analyses (pathology department of Santa-Maria-Nuova Hospital, Reggio Emilia, Italy).

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

9.

  : protein kinase B ALK: anaplastic lymphoma kinase CDDP: cis-diamminedichloroplatinum, cisplatin COPD: chronic obstructive pulmonary disease DMEM: Dulbecco/Vogt modified Eagle's minimal essential medium EGFR: epidermal growth factor receptor FBS: fetal bovine serum ICI: immune check-point inhibitor IHC: immunohistochemistry K-ras: Kirsten rat sarcoma LLC1: Lewis lung carcinoma 1 mTOR: mammalian target of rapamycin NAC: neoadjuvant chemotherapy NSCLC: non-small cell lung carcinoma PD-1/PD-L1: programmed cell death 1 and ligand PI3K: Phosphoinositide 3-kinase PR: partial response SD: stable disease 1. Introduction:

Figure 1 :Figure 2 :

 12 Figure 1: Influence of neoadjuvant cisplatin-based chemotherapy on PD-L1 expression in operated patients, IHC analyses.

Figure 3 :

 3 Figure 3: Cisplatin-induced PD-L1 expression in NSCLC cell-lines. Q-PCR quantification of PD-L1 mRNA after 24-hour incubation with cisplatin or equivalent concentrations of PBS (control) in (A) LNM-R (n=6), (B) A549 (n=8), and (C) LLC1 cells (n=8). (D) Western-blot analysis of PD-L1 protein after extraction from LNM-R (n=4), A549 (n=8), and LLC1 (n=5) cells incubated during 24 hours with PBS or 16 µM cisplatin, quantification is expressed as percentage of respective control. (E) Immunocytochemistry of A549 cells incubated during 24 hours with PBS or 16 µM cisplatin, PD-L1 protein (red labeling), nuclei (Hoechst blue labeling). Quantification of PD-L1 expression at the mRNA (F) and protein (G) levels after 24-hour incubation of LLC1 cells (n=4) with DMSO (control), cisplatin (8 µM), or cisplatin and AKT-inhibitor (MK2206, 1 µM).

Figure 4 :

 4 Figure 4: Cisplatin and anti-PD-L1 combined treatment reduced tumor growth, in the Lewis model.

Table 1 :

 1 Characteristics of patients included in the NAC cohort

	Variable	Number of patients (%)
	Gender
	male	29 (74.4%)
	female	10 (25.6%)
	Age
	≤ 60 years	25 (64.1%)
	> 60 years	14 (35.9%)
	Smoking
	Never	9 (23.1%)
	Current/former	30 (76.9%)
	COPD
	Yes	20 (51.3%)
	No	19 (48.7%)
	cStage
	Ia,b-IIa,b	0 (0.0%)
	IIIa	38 (97.4%)
	IIIb	1 (2.6%)
	IV	0 (0.0%)
	Type of NAC
	Cis + gemci	18 (46.2%)
	Cis + vino	13 (33.3%)
	Cis + other	8 (20.5%)
	Number of Cures
	2	16 (41.0%)
	3	16 (41.0%)
	4	7 (18.0%)
	Resection
	Lobectomy	20 (51.3%)
	Bilobectomy	4 (10.3%)

Cis: cisplatin; gemci: gemcitabine; vino: vinorelbine; ADK: adenocarcinoma ; SCC: squamous-cell carcinoma; LCNEC: large-cell neuroendocrine carcinoma ; yp : post-NAC pathological assessment.

Table 2 :

 2 Interrelationship between PD-L1 staining and clinicopathological features of NAC

	patients
	Variable	Mean (±SEM)	P-value	Proportion of ΔPD-L150 positive	P-value
		ΔPD-L1		patients in the category (%)
	Gender
	Male	13.7 (6.8)	0.78	20.7	0.66
	Female	17.6 (12.3)		30.0
	Age >60 years
	Yes	11.7 (8.4)	0.60	14.3	0.28
	No	17.8 (8.5)		28.0
	Smoker
	Current/former	14.7 (6.9)	0.84	23.3	0.66
	Never	17.7 (14.5)		22.2
	COPD
	Yes	22.6 (8.2)	0.23	30.0	0.25
	No	7.8 (9.2)		15.8
	Type of NAC
	Cis + gemci	16.7 (5.8)	0.67	22.2	0.80
	Cis + vino	8.6 (4.2)		20.0
	Cis + other	23.2 (8.3)		33.3
	Number of NAC cures
	<4	17.3 (6.2)	0.40	20.0	0.67
	≥4	1.8 (25.6)		23.5
	yp Viable tumor >50%
	Yes	30.8 (13.2)	0.09	50.0	0.02
	No	8.7 (6.3)		13.8
	yp Necrosis >30%
	Yes	6.6 (15.4)	0.47	22.2	0.66
	No	16.9 (6.3)		23.3
	yp Fibrosis >30%
	Yes	17.2 (6.9)	0.55	19.2	0.33
	No	9.6 (11.3)		30.8
	COPD: chronic obstructive pulmonary disease; Cis: cisplatin; gemci: gemcitabine; vino: vinorelbine
	yp: post-NAC pathological assessment.