Vijaya Sruthi

Retnakumar

Camille Chauvin

Jagadeesh Bayry
email: jagadeesh.bayry@crc.jussieu.fr

The implication of anti-PD-1 therapy in cancer patients for the vaccination against viral and other infectious diseases

Keywords: immune checkpoint, PD-1, COVID-19, Influenza, SARS-CoV-2, T cell exhaustion, cancer immunotherapy, vaccination, infection AE, adverse events, AP-1, activator protein-1, AU, arbitrary units, COVID-19, coronavirus disease 2019, CP, cancer patients, CRS, cytokine release syndrome, CTLA-4, cytotoxic T-lymphocyte-associated protein 4, ERD, enhanced respiratory syndrome, HC, healthy controls, HIV, human immunodeficiency virus, HPV, human papillomavirus, ICI, immune checkpoint inhibitors, ICP, immune checkpoint, IL, interleukin, irAEs, immunerelated adverse effects, ITIM, immunoreceptor tyrosine-based inhibitory motif, ITSM, RSV, respiratory syncytial virus, SARS-CoV, severe acute respiratory syndrome coronavirus, SHP, Src homology phosphatase, TCR, T cell receptor, Teff, effector T cells, Tfh, follicular helper T cell, Tregs, regulatory

in routine vaccination is indispensable for the protection of cancer patients, the impact of PD-1 blockade on vaccine responses against infectious agents requires careful consideration to avoid undesirable adverse effects that could impair the efficacy of anti-cancer treatment.

ABSTRACT

The phenomenon of 'T cell exhaustion', a state of T cell dysfunction observed during chronic infections and cancers, has been a major obstacle in mounting appropriate immune responses against infectious agents or tumor antigens. The exhausted T cells are characterized by poor effector functions mainly due to the overexpression of inhibitory receptors such as programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin-domain containing 3 (TIM3), lymphocyte activation gene 3 (LAG3), and T cell immunoreceptor with Ig and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), commonly referred to as immune checkpoint (ICP) molecules.

ICP blockade, especially of PD-1, which can potentially reverse T cell exhaustion and thereby re-stimulate the impaired immune system, is widely used in clinics as a promising therapeutic strategy for various cancers and is more recently being investigated in infectious diseases as well. In fact, cancer patients represent a population of immunocompromised individuals who are more susceptible to infections and associated complications, and thus the need for protective vaccinations against these diseases is of prime importance in this category. When it comes to vaccinating anti-PD-1-treated cancer patients against infectious agents, a special focus should be brought on the revived immune cells, which could be dynamically affected by the antigenic stimulation. However, since cancer patients are not generally included in clinical trials for designing vaccines against infectious diseases, the possible interaction between vaccine immune responses and ICP therapy is largely unexplored. Mechanistically, the reversal of T cell exhaustion by ICP in an otherwise immunocompromised population could be beneficial for the vaccine's efficacy, helping the immune system to mount a robust immune response. Nevertheless, patients with cancer undergoing anti-PD-1 blockade are known to experience immune-related adverse effects (irAEs). The risk of increasing the irAEs due to the overstimulation of the immune system during vaccination is a major concern. Therefore, while

Introduction

Cancer is a complex ecosystem and a dynamic milieu composed of different cell types interacting with each other partly via soluble factors. Tumor cells are surrounded by stromal cells and various subsets of immune cells that can communicate with them. The complexity of the tumor microenvironment justifies the inter-tumoral and inter-patient heterogeneity that still remains a hurdle in drawing a clear picture of cancer progression and successfully treating each individual patient [START_REF] Jamal-Hanjani | Translational implications of tumor heterogeneity[END_REF].

In the long history of cancer treatment, the most remarkable milestone during the past decade was the advent of immunotherapy. While conventional chemotherapy and radiotherapy directly target/kill cancer cells and induce immunogenic cell death, cancer immunotherapy is designed to boost and instruct the patient's immune system. In the domain of immunotherapy, immune checkpoint blockades that target cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/ programmed cell death-ligand 1 (PD-L1) that reverse the dormant state of the tumor-infiltrating immune cells have proven clinical success in the treatment of some refractory cancers. However, resistance to immune checkpoint (ICP) inhibition may also arise and efforts have been made to identify biomarkers that could help in the prediction of patients who will respond to immunotherapy (S. [START_REF] Wang | Cancer Immunotherapies: From Efficacy to Resistance Mechanisms -Not Only Checkpoint Matters[END_REF]. A metaanalysis has found that the objective response rates in anti-PD-1/PD-L1 treated patients reached only up to 29% in melanoma, 27% in lung cancer, and 21% in genitourinary cancer patients [START_REF] Chen | Response Efficacy of PD-1 and PD-L1 Inhibitors in Clinical Trials: A Systematic Review and Meta-Analysis[END_REF]. Aside from primary resistance that occurs rapidly in response to treatment, acquired resistance is also observed in the patients with at least 6 months of progression-free initial survival that limits the efficacy of anti-PD-1 therapy [START_REF] Dobosz | Challenges of the Immunotherapy: Perspectives and Limitations of the Immune Checkpoint Inhibitor Treatment[END_REF]. Many factors like the lack of tumor antigen expression and tumor immunogenicity linked to reduced mutation rates, the expression of additional checkpoint molecules by tumor cells, the presence of certain circulating noncoding RNAs that can regulate tumor immunogenicity, and the reduced diversity of the gut microbiota could contribute to the resistance to immunotherapy and the lack of success of PD-1 blockade [START_REF] Sun | Resistance to PD-1/PD-L1 blockade cancer immunotherapy: Mechanisms, predictive factors, and future perspectives[END_REF]. In parallel, anti-PD-1 treatment has been shown to apply a selective pressure on melanoma tumor cells leading to tumor evasion via mutations in MHC class I or IFN-g receptor signalling molecules [START_REF] Zaretsky | Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma[END_REF].

All these factors highlight the challenges to overcome for improving the outcomes of PD-1/PD-L1 immunotherapy.

One major factor that correlates with the response to immune checkpoint therapy is the variable density and variety of infiltrating immune cells in different tumors. Some tumors termed "hot tumors" are quite well infiltrated by immune cells to mount a strong inflammatory reaction against tumor antigens that is determinant for the establishment of an efficient anti-tumor response [START_REF] Duan | Turning Cold into Hot: Firing up the Tumor Microenvironment[END_REF]. However, some tumors that are less immunogenic, termed "cold tumors", do not succeed to attract immune cells, mainly effector T cells (Teff), or are predominantly infiltrated by regulatory cells, and consequently struggle to mount a robust antitumor immune response. Several factors, including the unavailability of some tumor antigens, a weakness in antigen presentation, an impaired T cell activation, and a Teff cell 'homing deficit' towards the target, are responsible for the lack of T cell infiltration at the cold tumor sites [START_REF] Bonaventura | Cold Tumors: A Therapeutic Challenge for Immunotherapy[END_REF]. Novel approaches to transform immune-excluded cold tumors into immune-inflamed hot tumors by improving T cell infiltration are currently of enormous interest to maximize the efficacy of cancer immunotherapy.

New cancer therapeutic strategies are emerging with the use of chimeric antigen receptor (CAR)-T cells, personalized cancer vaccines, and also combined therapies merging the effect of multiple ICP blockades or other strategies with ICP inhibition to synergistically improve the therapeutic outcome of cancer medicines [START_REF] Waldman | A guide to cancer immunotherapy: From T cell basic science to clinical practice[END_REF]. Besides, some attractive strategies lie in the possibility of combining immune checkpoint inhibitors (ICI) with an inflammatory boost stimulus into the tumor to maximize the effect of ICP blockade in the tumor core. Interestingly, influenza virus infection has been correlated with a decrease in cancerspecific mortality in lung cancer patients highlighting the benefit of local inflammation at the tumor site [START_REF] Newman | Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer[END_REF]. A similar synergistic impact is conceivable when administering vaccines against infectious diseases in cancer patients undergoing immune checkpoint therapy. On the other hand, owing to the heterogeneity of tumor microenvironment between tumors and between patients, the risk of some patients developing immune-related adverse events (irAEs) could be increased with a stronger boost of the immune response.

Due to their vulnerable immune status, cancer patients including the ones undergoing ICP therapies are necessarily prioritized for the vaccination campaigns for flu and coronavirus disease 2019 . However, data remain scarce on the possible reciprocal interaction between PD-1 blockade and vaccination. Intuitively, the reversal of T cell exhaustion by PD-1 blockade, that is beneficial to stimulate the anti-tumor immune response, can also amplify vaccine-related immunity. This review discusses the benefits and challenges of vaccinating cancer patients under immunotherapy against viral and other infectious diseases and novel opportunities in designing vaccination strategies combining immune checkpoint inhibitors.

PD-1/PD-L1 pathway

PD-1 interacts with its ligands PD-L1 and PD-L2 to maintain immune homeostasis by inducing central and peripheral tolerance. In contrast to the inhibitory effect of PD-1-PD-L1 interaction on T cell receptor (TCR) and costimulatory signals leading to apoptosis, anergy, and exhaustion of Teff cells [START_REF] Yokosuka | Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2[END_REF], the PD-1/PD-L1 axis induces continuous Foxp3 expression and proliferation in regulatory T cells (Tregs) [START_REF] Francisco | PD-L1 regulates the development, maintenance, and function of induced regulatory T cells[END_REF]. The tightly regulated expression of these molecules is essential for inhibiting self-reactive T cells and promoting Treg functions to prevent autoimmune responses [START_REF] Ghosh | A snapshot of the PD-1/PD-L1 pathway[END_REF]. However, the involvement of dysregulated PD-1/PD-L1 pathway is decisive in the reduction of anti-tumor response, and its overexpression on tumor-infiltrating T cells and tumor cells has been associated with poorer prognosis in cancer patients [START_REF] Zhang | Prognostic Significance of Programmed Cell Death 1 (PD-1) or PD-1 Ligand 1 (PD-L1) Expression in Epithelial-Originated Cancer: A Meta-Analysis[END_REF]. Recently, the PD-1/PD-L1 axis has also been found to be involved in the selective migration of Tregs and Teff through lymphatic endothelial cells in a mouse model of melanoma [START_REF] Piao | PD-L1 signaling selectively regulates T cell lymphatic transendothelial migration[END_REF].

PD-1, also known as CD279, was first discovered by Tasuku Honjo and colleagues in 1992, as a membrane protein that induces apoptosis in 2B4.11 cell line (a murine T-cell hybridoma) and interleukin-3 (IL-3)-deprived LyD9 cell line (a murine hematopoietic progenitor cell line) [START_REF] Ishida | Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death[END_REF]. Further studies carried out in PD-1 deficient mice have revealed the role of PD-1 in the induction of peripheral self-tolerance by negatively regulating immune responses [START_REF] Nishimura | Immunological studies on PD-1 deficient mice: Implication of PD-1 as a negative regulator for B cell responses[END_REF]. However, the nature of this inhibitory pathway became clear with the identification of B7-homologue 1 (B7-H1) -a member of the B7 family that consists of structurally related cell surface ligands that bind to lymphocyte co-stimulatory or co-inhibitory receptors-as the ligand of PD-1 (later named as PD-L1) [START_REF] Dong | B7-H1, a third member of the B7 family, costimulates T-cell proliferation and interleukin-10 secretion[END_REF][START_REF] Freeman | Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation[END_REF]. The second ligand of PD-1, termed PD-L2, was also discovered immediately after, that shared 40% sequence homology and overlapping functions with PD-L1 (Y. [START_REF] Latchman | PD-L2 is a second ligand for PD-1 and inhibits T cell activation[END_REF]. Similar to PD-1, PD-L1 deficient mice were also prone to autoimmune diseases (Y. E. [START_REF] Latchman | PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells[END_REF], demonstrating the critical negative regulatory role of the PD-1/PD-L1 pathway on effector T cell immune responses.

Although a low expression is found at the basal level, PD-1 is transcriptionally upregulated on T, B, and natural killer (NK) cells, dendritic cells (DCs), and macrophages upon antigen stimulation. While PD-L2 expression is limited mainly to antigen-presenting cells, PD-L1 is constitutively expressed or induced in numerous cell types including myeloid or lymphoid immune cells, normal epithelial cells, and cancer cells, conferring a more prominent role for PD-L1 than PD-L2 in tumor immunity [START_REF] Ghosh | A snapshot of the PD-1/PD-L1 pathway[END_REF]. Structurally, PD-1 consists of four domains, an immunoglobulin variable region (IgV), a transmembrane domain, immunoreceptor tyrosine-based inhibitory motifs (ITIMs), and immunoreceptor tyrosinebased switch motifs (ITSMs). The binding of PD-L1 to PD-1 induces the phosphorylation of intracellular ITIMs and ITSMs that further results in the recruitment of tyrosine acid phosphatase Src homology phosphatase 1 (SHP-1) and SHP-2 in close proximity to TCR. SHP-1 and SHP-2 dephosphorylate several targets involved in the TCR signalling pathways (Fig. 1) [START_REF] Salmaninejad | PD-1/PD-L1 pathway: Basic biology and role in cancer immunotherapy[END_REF][START_REF] Sharpe | The diverse functions of the PD1 inhibitory pathway[END_REF].

One of the main pathways involved in TCR signalling is the PI3K/AKT/mTOR pathway. Either the phosphoinositide 3-kinase (PI3K) can be dephosphorylated and inhibited directly by SHP-1/2, or SHP-1/2 can activate the phosphatase and tensin homolog (PTEN) via dephosphorylating the protein kinase casein kinase 2 (CK2), which further leads to the inhibition of PI3K. Another major pathway of TCR signalling is the RAS/MAPK/ERK pathway involved in cell proliferation and differentiation. SHP-1/2 directly targets rat sarcoma (RAS) that then leads to the inhibition of the RAS/MAPK/ERK pathway. The leukocytespecific tyrosine kinase (LCK) phosphorylates the proteins zeta chain of T-cell receptorassociated protein kinase (ZAP70), CD3-zeta (CD3Ϛ), and protein kinase Cθ (PKCθ) that continue to activate TCR signalling. PD-1 signalling can also inhibit the function of LCK via SHP1/2 recruitment, and hence modulate the TCR signalling downstream [START_REF] Sheppard | PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3ζ signalosome and downstream signaling to PKCθ[END_REF]. In contrast, PD-1 signalling via SHP1/2 is found to upregulate basic leucine zipper ATFlike (BATF), a member of the activator protein-1 (AP-1) transcription factor family, which can counteract the effector T cell transcriptional programs [START_REF] Quigley | Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF[END_REF]. In essence, the overexpression of PD-1/PD-L1 inhibits T cell growth, proliferation, and survival, through all these mechanisms, conferring them a dysfunctional or 'exhausted' phenotype in the tumor microenvironment (Fig. 1) [START_REF] Salmaninejad | PD-1/PD-L1 pathway: Basic biology and role in cancer immunotherapy[END_REF][START_REF] Sharpe | The diverse functions of the PD1 inhibitory pathway[END_REF].

Parallels between cancer and infection: immune checkpoints are altered in both

The phenomenon of T cell exhaustion that represents the functional impairment and terminal deletion of persistently stimulated antigen-specific T cells was first described during chronic viral infections [START_REF] Gallimore | Induction and Exhaustion of Lymphocytic Choriomeningitis Virus-specific Cytotoxic T Lymphocytes Visualized Using Soluble Tetrameric Major Histocompatibility Complex Class I-Peptide Complexes[END_REF], making the host susceptible to viral immune invasion.

Cancer shares many parallels with chronic infections due to the prolonged persistence of the antigens, and the crucial role of exhausted T cells in cancer progression has also been unfolded in later years (Fig. 2). The differentiation of the hyporesponsive tumor-specific CD8 + T lymphocytes starts early during tumorigenesis, and continuous antigen encounter and TCR stimulation in the tumor microenvironment are necessary to drive them towards exhaustion [START_REF] Schietinger | Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis[END_REF]. Several studies have found similar transcriptional signatures in the CD8 + T cells in cancer and chronic viral infection [START_REF] Dolina | CD8+ T Cell Exhaustion in Cancer[END_REF][START_REF] Khan | TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion[END_REF]. The AP-1 family transcription factors are found to be important drivers of the progression of various cancers due to their pleiotropic effects on cell proliferation, apoptosis, and T-cell activation, anergy or exhaustion (Fig. 1) [START_REF] Atsaves | AP-1 Transcription Factors as Regulators of Immune Responses in Cancer[END_REF]. Similarly, significant activation of AP-1 family members is observed during viral or bacterial infections to modulate the immune responses against them [START_REF] Quigley | Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF[END_REF][START_REF] Wang | Transcription factor complex AP-1 mediates inflammation initiated by Chlamydia pneumoniae infection[END_REF][START_REF] Yuan | Modulation of viral replication, apoptosis and antiviral response by induction and mutual regulation of EGR and AP-1 family genes during coronavirus infection[END_REF]. The analogous T cell phenotypes in cancer and infection could explain why cancer patients are more susceptible to antigen invasion when they are exposed to viruses or other infectious agents.

The onset of T cell exhaustion is characterized by the high expression of cell surface inhibitory receptors/ICP such as PD-1 that will inhibit the TCR signalling and effector functions by engaging the PD1-PD-L1 pathway. While few contemporary studies have been emerging

showing the beneficial effect of PD-1-PD-L1 blockade in potentiating tumor immunity, in 2006, Barber et al demonstrated for the first time that the reversal of T cell exhaustion is possible with PD-1-PD-L1 inhibition in chronic lymphocytic choriomeningitis virus (LCMV) infection [START_REF] Barber | Restoring function in exhausted CD8 T cells during chronic viral infection[END_REF]. Albeit the clinical application of PD-1 blockade has witnessed major breakthroughs in cancer therapy during the past decade, the advancement of PD-1 blockade for infectious diseases is in its infancy [START_REF] Hashimoto | CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions[END_REF]. The dysregulated expression of PD-1 or PD-L1 has been described during hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) infections [START_REF] Jubel | The Role of PD-1 in Acute and Chronic Infection[END_REF] and more recently in severe COVID-19 patients [START_REF] Bonam | SARS-CoV-2 Induces Cytokine Responses in Human Basophils[END_REF]Bonam, Chauvin, Mathew, et al., 2022;[START_REF] Bonam | Role of the PD-1 and PD-L1 axis in COVID-19[END_REF]. Bacteria and fungi could also induce PD-L1 on antigen presenting cells and in turn suppress Teff responses by promoting Tregs [START_REF] Karnam | Wnt-β-Catenin Signaling in Human Dendritic Cells Mediates Regulatory T-Cell Responses to Fungi via the PD-L1 Pathway[END_REF][START_REF] Periasamy | Programmed death 1 and cytokine inducible SH2containing protein dependent expansion of regulatory T cells upon stimulation With Mycobacterium tuberculosis[END_REF][START_REF] Stephen-Victor | Aspergillus fumigatus Cell Wall α-(1,3)-Glucan Stimulates Regulatory T-Cell Polarization by Inducing PD-L1 Expression on Human Dendritic Cells[END_REF]. Of note, experimental studies have shown an enhanced expression of PD-L1 in cancer cells upon exposure to infectious agents and aggravation of cancer in vivo when exposed to the infections [START_REF] Groeger | PD-L1 Up-Regulation in Prostate Cancer Cells by Porphyromonas gingivalis[END_REF][START_REF] Ren | P. gingivalis infection upregulates PD-L1 expression on dendritic cells, suppresses CD8+ T cell responses, and aggravates oral cancer[END_REF]. A number of clinical trials investigating PD-1 blockade are underway in these diseases and promising data seems to emerge [START_REF] Awadasseid | Potential protective role of the anti-PD-1 blockade against SARS-CoV-2 infection[END_REF][START_REF] Jubel | The Role of PD-1 in Acute and Chronic Infection[END_REF]. Besides suggesting the potential of the PD-1/PD-L1 pathway as a biomarker to predict disease progression and treatment outcome, these shreds of evidence emphasize the potential of PD-1 inhibition to tackle drug-resistant pathogens.

How does anti-PD-1 therapy modify the immune system? lessons learned from experimental models and cancer patients

As described above, the major mechanism of anti-PD-1 immunotherapy is to reinvigorate the CD8 + T cells that impart cytotoxic effects against tumor cells. Recent combination therapies with PD-1 blockade not only aim to reverse the exhaustion of CD8 + T cells but also to promote their expansion and survival. The engineered fusion of anti-PD-1 with an IL-15-IL-15Rα complex known as IL-15 superagonist (sIL-15) can efficiently induce tumor-specific CD8 + T cells and reduce metastasis while overcoming extensive peripheral NK cell activation and toxicity caused by IL-15 alone in various transplantable tumor models in mice [START_REF] Shen | An engineered concealed IL-15-R elicits tumor-specific CD8+T cell responses through PD-1-cis delivery[END_REF]. Similarly, PD-1 blockade + IL-2 combination therapy is also being investigated for cancer. It has been demonstrated recently in a mouse model of LCMV infection that combined anti-PD-1 and IL-2 therapy reverts the stem-like state of PD-1 + TCF1 + CD8 + T cells to support viral clearance [START_REF] Hashimoto | PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program[END_REF], suggesting the great potential of incorporating cytokines to modulate immune response with ICP therapy. In addition, PD-1 is expressed in tumor-infiltrating CD4 + T cells such as follicular helper T cells (Tfh), Tregs, NK cells, B lymphocytes, macrophages, DCs, and monocytes. The impact of PD-1 blockade on these cells has been insufficiently elucidated [START_REF] Han | PD-1/PD-L1 pathway: Current researches in cancer[END_REF]. Indeed, in parallel to counteracting CD8 + T cell exhaustion, PD-1 blockade has been shown to reduce the Treg infiltration in tumors [START_REF] Dyck | Anti-PD-1 inhibits Foxp3+ Treg cell conversion and unleashes intratumoural effector T cells thereby enhancing the efficacy of a cancer vaccine in a mouse model[END_REF]. In contrast, some other studies recall the role of anti-PD-1 in the activation of Tregs leading to tumor progression, highlighting the controversial contribution of PD-1 + Tregs in cancer [START_REF] Kamada | PD-1+ regulatory T cells amplified by PD-1 blockade promote hyperprogression of cancer[END_REF][START_REF] Kumagai | The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies[END_REF]. A recent study concluded that the unresponsiveness to ICIs combined with chemotherapy and the progression of metastatic triple-negative breast cancer were correlated with CD8 + T cell anergy, together with high levels of circulating antibody-secreting cells (ASCs), Tfh, and terminal NK cells before treatment [START_REF] Egelston | Abstract 5208: Circulating T cell: B cell: NK cell axis associated with response to pembrolizumab plus doxorubicin in patients with metastatic triple negative breast cancer[END_REF]. Despite the lack of antigen receptors, the role of NK cells is wellestablished in anti-tumor immunity mirroring cytotoxic T cells [START_REF] Laba | The depths of PD-1 function within the tumor microenvironment beyond CD8+ T cells[END_REF]. Moreover, anti-PD-1 therapy impacts the function and recruitment of Tfh cells [START_REF] Herati | PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine[END_REF] that provide essential help for B cells to generate antibodies. Potentially, the overactivation of Tfh and B cells could lead to autoreactive antibody production and the development of secondary autoimmunity.

It brings up the issue of irAEs, a parallel downside that occurs in cancer patients during ICI therapy due to the reactivation of the immune system. In addition to autoantibody production, various mechanisms such as inflammatory cell infiltration and pro-inflammatory cytokine production contribute to the development of irAEs. Some of the common irAEs generally appearing during ICP blockade therapy are linked with autoimmune responses like skin disorders, colitis, hepatitis, and thyroiditis [START_REF] Callahan | Targeting T Cell Co-receptors for Cancer Therapy[END_REF]. The incidence of irAEs reaches 26.82% (21.73-32.6) in any grade and 6.10% (4.85-7.64) in severe grade in a metaanalysis of patients treated with different anti-PD-1/anti-PD-L1 agents (P.-F. [START_REF] Wang | Immune-Related Adverse Events Associated with Anti-PD-1/PD-L1 Treatment for Malignancies: A Meta-Analysis[END_REF]. In fact, several studies have demonstrated that the development of irAEs is positively correlated with ICI treatment benefits and improved patient survival. Nevertheless, it is important to note that serious secondary effects that require treatment with immunosuppressants can counteract the efficacy of ICI therapy. Besides, it is necessary to optimally control the profound toxicities that can eventually lead to serious complications and organ failures, to improve the patient's quality of life and survival [START_REF] Iranzo | Overview of Checkpoint Inhibitors Mechanism of Action: Role of Immune-Related Adverse Events and Their Treatment on Progression of Underlying Cancer[END_REF].

Anti-PD-1 therapy in animal models and immune response to the vaccines

Few studies have been carried out in animal models to investigate the repercussion of PD-1 blockade towards immune response to vaccination against infectious agents. High expression levels of immune checkpoint molecules in immune cells are associated with the persistence of chronically-infecting pathogens and disease progression. Consequently, the combination of immune checkpoint blockade has emerged as an attractive strategy to enhance immune responses against pathogens. Human papillomavirus (HPV) infection is a common cause of certain types of cancers including cervical cancer, and head and neck cancers. The combination of HPV vaccination with PD-1 blockade has significantly controlled the tumor burden and improved the survival of C57BL/6 mice bearing HPV-expressing TC-1 tumors [START_REF] Peng | Development of DNA Vaccine Targeting E6 and E7 Proteins of Human Papillomavirus 16 (HPV16) and HPV18 for Immunotherapy in Combination with Recombinant Vaccinia Boost and PD-1 Antibody[END_REF]. Based on one hypothesis of shared immune response at the same site, an interesting study from Newman et al described the improvement of the antitumor response against lung melanoma with an intranasal challenge with influenza virus during PD-1 blockade in mice [START_REF] Newman | Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer[END_REF]. In contrast, influenza virus infection promoted melanoma growth in the skin, highlighting a diversion of the immune cells -particularly anti-tumor CD8 + T cells to the site of inflammation rather than at the tumor bed and the anti-cancer response could alternatively be rescued by PD-1 blockade [START_REF] Kohlhapp | Non-oncogenic Acute Viral Infections Disrupt Anticancer Responses and Lead to Accelerated Cancer-Specific Host Death[END_REF]. These results stress the prospects of coupling ICI therapy with an inflammatory trigger to reorientate the immune response towards the tumor site in the case of refractory cancers.

Towards the efforts to develop an ideal vaccine for HIV, PD-1 inhibition has been shown to improve the outcome of therapeutic vaccination and increase survival by inducing functional CD8 + T cells in a simian immunodeficiency virus infection model of Rhesus macaques [START_REF] Pan | Immune Protection of SIV Challenge by PD-1 Blockade During Vaccination in Rhesus Monkeys[END_REF][START_REF] Rahman | PD-1 blockade and vaccination provide therapeutic benefit against SIV by inducing broad and functional CD8 + T cells in lymphoid tissue[END_REF]. Enhancement of virus-specific T cell responses along with virus control was also observed when anti-PD-L1 was combined with therapeutic vaccination in chronic Friend retrovirus infection model of mice [START_REF] Knuschke | A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells[END_REF]. Blocking the PD-1/PD-L1 axis enhanced HIV-1 Gag-specific CD8 + T cell responses following vaccination of mice with dendritic cell-directed lentiviral vaccines [START_REF] Dai | PD-1/PD-L1 blockade can enhance HIV-1 Gag-specific T cell immunity elicited by dendritic cell-directed lentiviral vaccines[END_REF]. Another study carried out in HLA transgenic rabbits has demonstrated that synergistic blockade of PD-1 and LAG-3 improved the therapeutic vaccination efficacy of herpes simplex virus [START_REF] Roy | Blockade of PD-1 and LAG-3 Immune Checkpoints Combined with Vaccination Restores the Function of Antiviral Tissue-Resident CD8 + T RM Cells and Reduces Ocular Herpes Simplex Infection and Disease in HLA Transgenic Rabbits[END_REF]. PD-1 deficiency and PD-1 blockade following Streptococcus pneumonia vaccination also significantly increased the protective IgG responses in mice [START_REF] Mckay | PD-1 suppresses protective immunity to Streptococcus pneumoniae through a B cellintrinsic mechanism[END_REF]. Similarly, PD-1 deficiency in mice augments the germinal center B cell and plasmodium-specific-Tfh cell responses during malaria vaccination, suggesting that PD-1 blockade could be effectively combined with malaria vaccination as well [START_REF] Liu | PD-1 Deficiency Enhances Humoral Immunity of Malaria Infection Treatment Vaccine[END_REF].

PD-1 blockade may not benefit each and every vaccination against infectious diseases.

Management of respiratory syncytial virus (RSV) infection is still an unresolved issue since inactivated RSV vaccine is shown to induce enhanced respiratory syndrome (ERD) upon subsequent viral infection. Cotton rats (Sigmodon hispidus) serve as an excellent animal model for RSV infection, and this model replicates the RSV vaccine-induced ERD. Studies carried out in this model have shown that the development of ERD was found to be associated with low levels of pulmonary PD-1 expression [START_REF] Muralidharan | PD-1 of Sigmodon hispidus: Gene identification, characterization and preliminary evaluation of expression in inactivated RSV vaccine-induced enhanced respiratory disease[END_REF]. Hence, in this case, PD-1 blockade would be more detrimental than beneficial and alternative strategies need to be devised to avoid the over-activation of the immune system in response to RSV vaccination.

Similarly, PD-1 blockade has been found to exacerbate Mycobacterium tuberculosis (TB) infection in Rhesus macaque [START_REF] Kauffman | PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques[END_REF]. It is necessary to take these findings into careful consideration when administering anti-PD-1 therapy to cancer patients who had prior exposure to TB.

Anti-PD-1 therapy alters immune responses during vaccination against infectious diseases in humans

Cancer patients are at higher risk of becoming seriously ill if they catch infections (flu, measles, COVID-19, and others), firstly because of their impaired immune system and also because their immune response should concentrate on fighting the tumor rather than resolving the infection-induced chronic inflammation. Vaccine antigens stimulate a number of cells of the innate and adaptive immune systems to generate the cellular and humoral responses postvaccination. Since PD-1 is expressed in Teff cells, Tfh cells, and B cells that are important in generating cellular and antibody responses, anti-PD-1 therapy could dynamically affect the post-vaccination immune responses. Theoretically, PD-1 blockade could be beneficial, augmenting antibody generation or cellular responses to vaccination, and conferring greater protection from infection. Yet, there are several pitfalls in this assumption including the risk of increasing irAEs due to the hyperstimulation of the immune system in certain patients (Figure 3). Live-attenuated vaccines including measles, rotavirus, and chickenpox vaccines are not recommended for cancer patients due to the risk of viral replication and infection in vulnerable individuals (Ariza-Heredia & Chemaly, 2015). However, influenza vaccines are generally subunit protein vaccines and although they are limited by their low efficacy, it is safe to administer them in immunocompromised individuals in general. Besides, the COVID-19 era popularized the use of mRNA vaccines that are more potent than other vaccine strategies without imposing significant risks on a majority of individuals. Since cancer patients are not included in investigational trials for vaccine development, there is not enough clinical evidence so far to demonstrate the interaction between ICI therapy and different types of vaccines against various pathogens. Only a few retrospective studies have investigated the interaction between ICI therapy and vaccination for influenza and severe acute respiratory syndrome coronavirus (SARS-CoV)-2 in cancer patients (Table 1 and references therein).

Influenza vaccination in patients undergoing anti-PD-1 therapy: a long-standing debate

Annual influenza vaccination is recommended for cancer patients who are particularly at increased risk of influenza infection-related complications due to their underlying disease or cancer-directed treatments. Despite their immunosuppressive background, several studies have found that cancer patients can mount an immune response against influenza vaccines. However, the immunogenicity differs according to the type of cancer treatment received by the patients, and whether the generated response can fully protect them from influenza infection and associated complications is still controversial. Cancer-induced immunosuppression or the use of conventional cytotoxic or immunosuppressive therapies is expected to counteract the cellular and humoral immune responses to influenza vaccination. Hence, patients undergoing chemotherapy have been shown to experience lower protection than healthy individuals. In contrast, higher seroprotection and seroconversion rates were demonstrated in ICI-treated cancer patients compared to cytotoxic chemotherapy groups according to a previous study [START_REF] Keam | Immunogenicity of Influenza Vaccination in Patients with Cancer Receiving Immune Checkpoint Inhibitors[END_REF]. Follow-up studies by the same group have also demonstrated higher cellmediated immune responses for both CD4 + and CD8 + T cells in ICI-treated individuals compared to chemotherapy groups, consistent with the immune-stimulating capacity of anti-PD-1 therapy [START_REF] Kang | Cell-Mediated Immunogenicity of Influenza Vaccination in Patients With Cancer Receiving Immune Checkpoint Inhibitors[END_REF]. More recently, Herati et al. have shown that the Tfh-B cell axis was altered during the generation of immune responses to influenza vaccination in anti-PD-1 treated cancer patients [START_REF] Herati | PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine[END_REF]. Tfh cells have been shown to play a major role in the generation of high-affinity antibody responses following seasonal influenza vaccination with evidence of circulating Tfh1 cells communicating with influenza-specific memory B cells and promoting their differentiation into plasmablasts [START_REF] Ueno | Tfh cell response in influenza vaccines in humans: What is visible and what is invisible[END_REF]. The increase in Tfh activation and plasmablast frequency suggests an enhanced germinal center activity and B cell maturation, and was associated with an increase in the fold induction of hemagglutinin inhibitory antibody titers compared to baseline in anti-PD-1-treated individuals.

Nevertheless, a qualitative functional impairment was observed in the influenza antibodies generated in anti-PD-1 treated patients that resulted in similar endpoint seroprotection rates compared to healthy individuals [START_REF] Herati | PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine[END_REF].

In addition to vaccine efficacy, concerns were raised about the risk of irAEs in ICI-treated patients as a result of influenza vaccine-induced immune responses in several studies. Despite that, a recent systematic meta-analysis revealed that the vaccinated patients reported a slightly lower rate of irAEs (gastrointestinal, endocrinal, pulmonary, cutaneous or rheumatic) compared to unvaccinated patients (32% versus 41%, respectively), and seroprotection rates were comparable between healthy and ICI-treated cancer patients, confirming that influenza vaccination increases the survival of patients under PD-1 blockade therapies without having any detrimental effects in terms of safety [START_REF] Lopez-Olivo | Safety and Efficacy of Influenza Vaccination in Patients Receiving Immune Checkpoint Inhibitors. Systematic Review with Meta-Analysis[END_REF][START_REF] Valachis | Improved survival without increased toxicity with influenza vaccination in cancer patients treated with checkpoint inhibitors[END_REF]. Still, some unresolved questions remain regarding the protection of vaccinated cancer patients during the occurrence of flu infection and the reciprocal effect of vaccine-induced immune responses on the anti-tumor response and survival of the patients. It has been shown that seasonal flu infection can convert cold tumors into hot tumors in a mouse model of pulmonary melanoma and the combination of PD-1 blockade resulted in an increase in the antitumor response [START_REF] Newman | Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer[END_REF]. In this context, a commercial unadjuvanted inactivated flu shot (FluVx) could be synergized with PD-L1 blockade to reduce tumor growth while PD-L1 used alone failed to do so [START_REF] Newman | Intratumoral injection of the seasonal flu shot converts immunologically cold tumors to hot and serves as an immunotherapy for cancer[END_REF]. This attractive strategy may help in treating ICI-resistant tumors. Long-term follow-up studies are required to address these issues in the patients.

Impact of anti-PD-1 therapy in cancer patients to COVID-19 vaccines

The global threat of the COVID-19 pandemic necessitated the rapid development of vaccines and massive vaccination campaigns prioritizing immunocompromised individuals including cancer patients. However, cancer patients were not included in the clinical trials for vaccine development [START_REF] Yap | SARS-CoV-2 vaccination and phase 1 cancer clinical trials[END_REF] and minimal data has emerged so far regarding the interference between COVID-19 vaccines and ICI therapy. Although cancer patients under active immunotherapy showed seropositivity after the second dose of BNT162b2 (mRNA vaccine) or AZD1222 vaccine (or ChAdOx1, a viral vectored vaccine), the anti-SARS-CoV-2 IgG titers or neutralizing antibody titers were lower compared to healthy controls [START_REF] Massarweh | Evaluation of Seropositivity Following BNT162b2 Messenger RNA Vaccination for SARS-CoV-2 in Patients Undergoing Treatment for Cancer[END_REF][START_REF] Terpos | SARS-CoV-2 Neutralizing Antibodies Kinetics Postvaccination in Cancer Patients under Treatment with Immune Checkpoint Inhibition[END_REF]). An additional booster dose compensates for the delayed response to confer similar protection between ICI-treated patients and healthy individuals [START_REF] Massarweh | Evaluation of Seropositivity Following BNT162b2 Messenger RNA Vaccination for SARS-CoV-2 in Patients Undergoing Treatment for Cancer[END_REF]. Nonetheless, patients treated with immunotherapy developed a stronger anti-SARS-CoV-2 humoral response as compared to patients treated with chemotherapy or targeted therapies [START_REF] Fenioux | SARS-CoV-2 Antibody Response to 2 or 3 Doses of the BNT162b2 Vaccine in Patients Treated With Anticancer Agents[END_REF]. Another study evaluated the risk factors for negative seroconversion in vaccinated cancer patients as male sex and active treatment (chemotherapy, immunotherapy, biological therapy alone, and chemotherapy plus biological therapy) [START_REF] Cavanna | COVID-19 vaccines in adult cancer patients with solid tumours undergoing active treatment: Seropositivity and safety. A prospective observational study in Italy[END_REF]. Two studies from the same group evaluated the neutralizing antibody (NAbT) levels in patients with solid and haematological tumors and under different therapies including immunotherapies (Fendler, Shepherd, Au, Wu, et al., 2022;[START_REF] Fendler | Immune responses following third COVID-19 vaccination are reduced in patients with hematological malignancies compared to patients with solid cancer[END_REF]. As what was observed in healthy individuals by others, most of the patients with cancer in the cohort exhibited a time-dependent decline in NAbT during follow-up and lacked detectable NAbT against the Variants of Concerns (VOCs) following two vaccine doses, independently of the vaccine type (BNT162b2 or ChAdOx1). However, a third dose of BNT162b2 in solid cancer patients resulted in a significant increase in NAbT against Omicron. On the other hand, patients with haematological malignancies developed an impaired response to VOCs even after a third vaccination. Overall, the proportion of patients with solid cancer, including the patients treated with ICP blockade, who developed NAbT was comparable to individuals without cancer after a third vaccination (Fendler, Shepherd, Au, Wu, et al., 2022). Another recent study in a small cohort has reported that cancer patients mount both humoral and T cell responses to COVID-19 vaccination but was independent of their response to ICI therapy [START_REF] Sisteré-Oró | Brief Research Report: Anti-SARS-CoV-2 Immunity in Long Lasting Responders to Cancer Immunotherapy Through mRNA-Based COVID-19 Vaccination[END_REF].

Short-term safety of the BNT162b2 vaccine was assessed in ICI-treated patients at 17-21 days after the first dose and 12-31 days after the second dose. The data revealed that the vaccinerelated systemic side effects were comparable between the ICI-treated groups and healthy controls. Moreover, no new irAEs or exacerbations of previously existing irAEs were reported in this study [START_REF] Ohuchi | Fulminant type 1 diabetes mellitus triggered by coronavirus disease 2019 vaccination in an advanced melanoma patient given adjuvant nivolumab therapy[END_REF]. Nevertheless, few case studies reported the rare occurrence of some irAEs such as hepatitis, colitis, autoimmune type I diabetes, or cytokine release syndrome (CRS) in cancer patients undergoing immunotherapy post-COVID-19 vaccination [START_REF] Au | Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2[END_REF][START_REF] Lasagna | Development of hepatitis triggered by SARS-CoV-2 vaccination in patient with cancer during immunotherapy: A case report[END_REF][START_REF] Ohuchi | Fulminant type 1 diabetes mellitus triggered by coronavirus disease 2019 vaccination in an advanced melanoma patient given adjuvant nivolumab therapy[END_REF]. Also an exacerbation of some irAEs, for instance, grade 4 skin rash, has been observed in cancer patients under ICP blockade following COVID-19 vaccination [START_REF] Hussain | Severe cutaneous adverse reaction following COVID-19 vaccination and immunotherapy: A second hit?[END_REF]. A patient with non-small cell lung cancer who developed severe toxic epidermal necrolysis induced by Pembrolizumab was successfully treated with intravenous immunoglobulin (IVIG) therapy, suggesting the potential use of IVIG to treat irAEs [START_REF] Galeotti | IVIG-mediated effector functions in autoimmune and inflammatory diseases[END_REF][START_REF] Kian | Intravenous immunoglobulin efficacy on pembrolizumab induced severe toxic epidermal necrolysis[END_REF]. Hence, to be on the safer side, the interactions between anti-PD-1 immunotherapy and COVID-19 vaccination should be carefully considered from both sides. Recommendations from an international group of medical oncologists highlighted the necessity to avoid the administration of anti-cancer investigational medicinal products (IMP) until 2-4 weeks after the second dose of COVID-19 vaccine, especially for those having a risk of CRS [START_REF] Au | Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2[END_REF]. Vaccine administration should probably be avoided in patients experiencing cancer IMP trial-associated irAEs until the events are markedly resolved.

A prospective multicenter, longitudinal, multi-cohort study known as VOICE (vaccination against COVID in cancer) including patients with solid cancer malignancies undergoing active cancer therapy is underway to assess the immune responses to mRNA-1273 SARS-CoV-2 vaccine from Moderna. This trial intends to follow up on the incidence and severity of COVID-19 after vaccination in these patients, in addition to in-depth studies on the strength and longevity of the antibody and T cell responses to the vaccine and the vaccine side effects [START_REF] Van Der Veldt | COVID-19 vaccination: The VOICE for patients with cancer[END_REF]. The initial data emerging from this study confirm the safety and adequate antibody responses to vaccination in a larger cohort of cancer patients undergoing different types of therapy [START_REF] Oosting | mRNA-1273 COVID-19 vaccination in patients receiving chemotherapy, immunotherapy, or chemoimmunotherapy for solid tumours: A prospective, multicentre, non-inferiority trial[END_REF], and follow-up studies are ongoing to compare the longevity of this protection. Nevertheless, the existing data seems to guarantee that the benefits outweigh the risks.

Concluding remarks

Although it remains necessary that cancer patients should be protected against infectious diseases by vaccination, in view of some rare cases of adverse side effects like CRS [START_REF] Au | Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2[END_REF], identification of biomarkers to predict the patients with a higher risk of developing side effects is necessary. Indeed, Herati et al. highlighted a correlation between the irAEs and Tfh responses in anti-PD-1-treated cancer patients that can be useful to anticipate the occurrence of deleterious side effects [START_REF] Herati | PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine[END_REF]. Monitoring the level of circulating Tfh numbers could have a predictive value in many other pathologies as well since, they were found to be upregulated in the blood of patients with autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis [START_REF] Gensous | T Follicular Helper Cells in Autoimmune Disorders[END_REF].

The consequences of vaccinating cancer patients who are resistant to immunotherapy is another area that requires in-depth discussion. The complexity of factors and mechanisms underlying resistance to ICI treatment is further enhanced by patient-to-patient variability as well as inter and intra-tumor heterogeneity [START_REF] Hu-Lieskovan | Addressing resistance to immune checkpoint inhibitor therapy: An urgent unmet need[END_REF]. Various PD-1/PD-L1 independent immune-escape mechanisms could contribute to an immunosuppressive TME (e.g., myeloidderived suppressor cells, M2 polarized tumor-associated macrophages, N2 neutrophils), which has a major role in the development of immunotherapeutic resistance and hence strategies such as combination therapies to evade these mechanisms are essential [START_REF] Jenkins | Mechanisms of resistance to immune checkpoint inhibitors[END_REF]. The combination of anti-PD-1 therapy with an intra-tumoral injection of antigenic peptide-coated BCG has been found to improve the anti-tumoral response by reducing immunosuppressive cells and increasing the tumor-infiltrating T cells in cancer models of mice [START_REF] Ylösmäki | Novel personalized cancer vaccine platform based on Bacillus Calmette-Guèrin[END_REF]. These types of immunomodulatory agents, especially infectious disease vaccines, which promising results open the way for the use of mRNA to treat cancer and, more importantly, to combine mRNA cancer vaccine to mRNA COVID-19 vaccine to promote the anti-cancer response and minimize the side effects. However, unlike other vaccines for infectious diseases, mRNA vaccine for COVID-19 did not undergo rigorous randomized clinical trials and reports on higher risk of cardiac inflammation in vaccinated population are emerging [START_REF] Pillay | Incidence, risk factors, natural history, and hypothesised mechanisms of myocarditis and pericarditis following covid-19 vaccination: Living evidence syntheses and review[END_REF]. Therefore, careful analysis of all the clinical parameters and adverse events is critical.

Also, in order to optimize the effect of vaccination for the cancer patient under ICI treatment, another option could be to inject the shot against the infectious agent closer to the tumor site depending on the type of cancer. This question is rationalized to avoid the diversion of the immune response to the area of vaccine-induced inflammation rather than to the tumor bed.

With the development of new vaccine formulations, the mode of administration could be improved/adapted as well. The data emerging from influenza and COVID-19 vaccine studies open several opportunities and challenges towards the development of optimized vaccination strategies against viral and other infectious diseases suitable for cancer patients and more generally for immunocompromised individuals having other comorbidities, to provide the best outcome without compromising the safety or the efficacy of anti-cancer treatment.

The lessons learned from cancer patients under ICI therapy could be extrapolated to look at the importance of ICIs in designing novel vaccines or therapeutic strategies for other infectious diseases as well. Promising data have emerged in animal studies for several difficult-to-treat chronic pathogens such as HIV and hepatitis with ICP blockade therapy. Indeed, HIV patients are at a higher risk of developing cancer and viral hepatitis is common among patients with liver, gastrointestinal, head and neck, and lung cancers [START_REF] Ramsey | Prevalence of Hepatitis B Virus, Hepatitis C Virus, and HIV Infection Among Patients With Newly Diagnosed Cancer From Academic and Community Oncology Practices[END_REF]. There are reports

showing that the application of anti-PD-1 therapy in cancer patients living with HIV or hepatitis infection leads to a decrease in viral loads, thus emphasizing the prospects of PD-1 blockade in treating diseases caused by these pathogens [START_REF] Tsiakos | Programmed Cell Death Protein 1 Axis Inhibition in Viral Infections: Clinical Data and Therapeutic Opportunities[END_REF]. The clinical application of these data is progressing with extreme caution due to the potential side effects of ICIs in chronically-infected patients [START_REF] Hashimoto | CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions[END_REF]. Strategies to predict the occurrence of irAEs would help to resolve this problem and to enhance the future of ICI therapy in cancer and infectious diseases.

In conclusion, scrutinizing vaccine-induced responses in ICI-treated cancer patients sheds light on the grey areas in vaccinating immunocompromised individuals and provides futuristic insights into the potential of targeting ICPs in infectious diseases. Nevertheless, some questions remain to be answered. What are the risks and benefits of vaccinating cancer patients resistant to immunotherapy treatment? What is the best window to vaccinate cancer patients undergoing ICP blockade? How can we easily predict the occurrence/exacerbation of irAEs in cancer patients while vaccinating for infectious diseases? The discovery of effective and accurate predictive markers of response to immunotherapy and over-activation of immune responses is urgently needed to address these challenges.

  can reprogram the TME are in the spotlight for overcoming ICI treatment resistance in recent years and hence indicate the additional benefit of vaccinating cancer patients who are resistant to anti-PD-1 therapy. In addition, it is important to consider the vaccine development strategy for cancer patients undergoing immunotherapy. Does the type of immune response generated by different vaccine strategies determine the type and severity of adverse effects observed in cancer patients? The existing Influenza protein subunit vaccines predominantly generate CD4 + T cell-mediated humoral responses, whereas the COVID-19 epoch benefited significantly from recent breakthroughs in the mRNA vaccine technology that generates the most potent immune response boosting all arms of the immune system including humoral (CD4 + T cell), CD8 + T cell and innate immune responses. Global efforts are ongoing in the development of singleshot combo mRNA vaccines for both COVID-19 and the flu. Would this shortcut approach also bypass or minimize the risk of some adverse events in immunocompromised individuals? Moderna and Merck recently released some encouraging results on their Phase IIb clinical trial studying the efficacy of mRNA cancer vaccine combined with Pembrolizumab in melanoma patients (KEYNOTE-942; https://clinicaltrials.gov/ct2/show/NCT03897881) (https://www.science.org/content/blog-post/moderna-and-merck-are-better-right). The resultsshow a reduced risk of recurrence or death by 44% in patients with advanced melanoma. These

Fig. 1 :

 1 Fig. 1: PD-1/PD-L1 signalling pathway. PD-L1 expressed on the surface of APCs or cancer

Fig. 2 :Fig. 3 :

 23 Fig. 2: Parallel phenotypes of cancer and chronic infection. Tumor antigens and chronic

Table 1 .

 1 Summary of studies testing the safety and efficacy of vaccination against viral diseases in cancer patients undergoing immunotherapy with immune checkpoint inhibitors.

	Abbreviations: AE, adverse event; AU, arbitrary units; CNS, central nervous system; CP,
	cancer patients; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; HC, healthy controls;
	ICI, immune checkpoint inhibitor; irAE, immune-related adverse events; N.R., not reported;
	NAbT, neutralizing antibody titer; NSCLC, non-small cell lung carcinoma; OS, overall
	survival, PD-1, programmed cell death protein 1; PD-L1, programmed cell death protein ligand
	1; PFS, progression-free survival; Tfh, follicular helper T cells; vs., versus; WT, wildtype.

Acknowledgments

References Acknowledgments Sruthi Vijaya Retnakumar and Camille Chauvin are supported by post-doc fellowships from the INDIGO project (European Union Horizon 2020: H2020-SC1-2019-874653-INDIGO and the Department of Biotechnology, Ministry of Science and Technology, Government of India: BT/IN/EU-INF/17/GK/19-20) and l'Agence Nationale de la Recherche, France (ANR-19-CE17-0021-BASIN) respectively. Views and opinions expressed are however those of the authors only and do not necessarily reflect those of the funding agencies.

Conflict of Interest Statement

The authors declare that there are no conflicts of interest. All groups achieved similar endpoint seroprotection. However, fold induction of antibody responses was significantly higher in anti-PD-1 treated CP compared to others, reflecting lower baseline and qualitative impairment of antibodies in the former group. [START_REF] Herati | PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine[END_REF]