Peripheral Innate Lymphoid Cells Are Increased in First Line Metastatic Colorectal Carcinoma Patients: A Negative Correlation With Th1 Immune Responses

Several distinct innate lymphoid cell (ILC) populations have been recently identified and shown to play a critical role in the immediate immune defense. In the context of tumors, there is evidence to support a dual role for ILCs with pro-or antitumor effects, depending on the ILC subset and the type of cancer. This ambivalent role has been particularly well-described in colorectal cancer models (CRC), but the presence and the evolution of ILCs in the peripheral blood of metastatic CRC (mCRC) patients have not yet been explored. Here, we investigated the distribution of ILC subsets in 96 mCRC patients who were prospectively included in the "Epitopes-CRCO2" trial. Peripheral bloodmononuclear cells (PBMCs) were analyzed by flow cytometry at metastatic diagnosis and after 3-months of treatment. The treatments consisted of Oxaliplatin-based chemotherapies for 76% of the patients or Folfiri (5FU, Irinotecan) chemotherapies for 14% of patients. Compared to healthy donors, the frequency of total ILCs was dramatically increased at metastatic diagnosis. CD56(+) ILC1-like cells were expanded, whereas ILC2, NCR- ILCP and NCR+ ILCP subsets were decreased. Combined analysis with the systemic anti-telomerase hTERT Th1 CD4 response revealed that patients with low anti-TERT Th1 CD4 responses had the highest frequencies of total ILCs at diagnosis. Of those, 91% had synchronous metastases, and their median progression-free survival was 7.43 months (vs. 9.17 months for the other patients). In these patients, ILC1 and ILC2 were significantly decreased, whereas CD56(+) ILC1-like cells were significantly increased compared to patients with low frequency of total ILCs and high anti-TERT responses. After treatment, the NCR+ ILCP were further decreased irrespective of the chemotherapy regimen, whereas the balance between ILC1 and CD56(+) ILC1-like cells was modulated mainly by the Folfiri regimen in favor of ILC1. Altogether our results describe the effects of different chemotherapies on ILCs in mCRC patients. We also establish for the first time a link between frequency of ILCs and anti-tumor CD4 T cell responses in cancer patients. Thus, our study supports an interest in monitoring ILCs during cancer therapy to possibly identify predictive biomarkers in mCRC

Interest of Tumor-Specific CD4 T Helper 1 Cells for Therapeutic Anticancer Vaccine

Nowadays, immunotherapy represents one promising approach for cancer treatment. Recently, spectacular results of cancer immunotherapy clinical trials have confirmed the crucial role of immune system in cancer regression. Therapeutic cancer vaccine represents one widely used immunotherapy strategy to stimulate tumor specific T cell responses but clinical impact remains disappointing in targeting CD8 T cells. Although CD8 T cells have been initially considered to be the main protagonists, it is now clear that CD4 T cells also play a critical role in antitumor response. In this article, we discuss the role of tumor antigen-specific CD4 T cell responses and how we can target these cells to improve cancer vaccines

Characterization of atypical T cells generated during ex vivo expansion process for T cell-based adoptive immunotherapy

Engineered T cell-based adoptive immunotherapies met promising success for the treatment of hematological malignancies. Nevertheless, major hurdles remain to be overcome regarding the management of relapses and the translation to solid tumor settings. Properties of T cell-based final product should be appropriately controlled to fine-tune the analysis of clinical trial results, to draw relevant conclusions, and finally to improve the efficacy of these immunotherapies. For this purpose, we addressed the existence of atypical T cell subsets and deciphered their phenotypic and functional features in an HPV16-E7 specific and MHC II-restricted transgenic-TCR-engineered T cell setting. To note, atypical T cell subsets include mismatched MHC/co-receptor CD8 or CD4 and miscommitted CD8+ or CD4+ T cells. We generated both mismatched and appropriately matched MHC II-restricted transgenic TCR on CD8 and CD4-expressing T cells, respectively. We established that CD4+ cultured T cells exhibited miscommitted phenotypic cytotoxic pattern and that both interleukin (IL)-2 or IL-7/IL-15 supplementation allowed for the development of this cytotoxic phenotype. Both CD4+ and CD8+ T cell subsets, transduced with HPV16-E7 specific transgenic TCR, demonstrated cytotoxic features after exposure to HPV-16 E7-derived antigen. Ultimately, the presence of such atypical T cells, either mismatched MHC II-restricted TCR/CD8+ T cells or cytotoxic CD4+ T cells, is likely to influence the fate of patient-infused T cell product and would need further investigation

Harnessing Antitumor CD4+ T Cells for Cancer Immunotherapy

Over the past decades, CD4+ T cells have been considered as a supporting actor in the fields of cancer immunotherapy. Until recently, accumulating evidence has demonstrated the critical role of CD4+ T cells during antitumor immunity. CD4+ T cells can either suppress or promote the antitumor cytotoxic CD8+ T cell responses, either in secondary lymphoid organs or in the tumor. In this review, we provide an overview of the multifaceted role of different CD4+ T cell subsets in cancer immune response and their contribution during cancer therapies. Specifically, we focus on the latest progress regarding the impact of CD4+ T cell modulation on immunotherapies and other cancer therapies and discuss the prospect for harnessing CD4+ T cells to control tumor progression and prevent recurrence in patients

The ATG8 Family Proteins GABARAP and GABARAPL1 Target Antigen to Dendritic Cells to Prime CD4+ and CD8+ T Cells

Vaccine therapy is a promising method of research to promote T cell immune response and to develop novel antitumor immunotherapy protocols. Accumulating evidence has shown that autophagy is involved in antigen processing and presentation to T cells. In this work, we investigated the potential role of GABARAP and GABARAPL1, two members of the autophagic ATG8 family proteins, as surrogate tumor antigen delivery vectors to prime antitumor T cells. We showed that bone marrow-derived dendritic cells, expressing the antigen OVALBUMIN (OVA) fused with GABARAP or GABARAPL1, were able to prime OVA-specific CD4+ T cells in vitro. Interestingly, the fusion proteins were also degraded by the proteasome pathway and the resulting peptides were presented by the MHC class I system. We then asked if the aforementioned fusion proteins could improve tumor cell immunogenicity and T cell priming. The B16-F10 melanoma was chosen as the tumor cell line to express the fusion proteins. B16-F10 cells that expressed the OVA-ATG8 fused proteins stimulated OVA-specific CD8+ T cells, but demonstrated no CD4+ T cell response. In the future, these constructions may be used in vaccination trials as potential candidates to control tumor growth

Immunogenicity of a recombinant lentiviral vector carrying human telomerase tumor antigen in HLA-B*0702 transgenic mice.

International audienceOver expression of telomerase represents a hallmark of cancer cells and the induction of T cell immunity against this universal tumor antigen have gained promising interest for anticancer immunotherapy. In this study we evaluated a recombinant lentiviral vector expressing the human telomerase reverse transcriptase (lv-hTERT) vaccination in the humanized HLA-B*0702 transgenic (HLA-B7 Tg) mice. A single lv-hTERT vector immunization induces potent and broad HLA-B7-restricted CTL responses against hTERT. Unlike conventional hTERT peptide or DNA immunization, the lv-hTERT vector triggers high and sustained IFN-gamma producing CD8(+) T cell responses in HLA-B7 Tg mice. The avidity and in vivo cytotoxicity of CD8(+) T cells were stronger in lv-hTERT vector-immunized mice than in hTERT peptide or DNA vaccinated groups. The study also showed that the use of prime-boost vaccination drastically improved the magnitude and strength of lentivector-primed CD8(+) T cells. Our data indicated that lentiviral delivery of hTERT is suitable for enhancing cellular immunity against hTERT and offers a promising alternative for telomerase-based cancer vaccine

Enhanced emergence of antibiotic-resistant pathogenic bacteria after in vitro induction with cancer chemotherapy drugs

International audienceBACKGROUND:Infections with antibiotic-resistant pathogens in cancer patients are a leading cause of mortality. Cancer patients are treated with compounds that can damage bacterial DNA, potentially triggering the SOS response, which in turn enhances the bacterial mutation rate. Antibiotic resistance readily occurs after mutation of bacterial core genes. Thus, we tested whether cancer chemotherapy drugs enhance the emergence of resistant mutants in commensal bacteria.METHODS:Induction of the SOS response was tested after the incubation of Escherichia coli biosensors with 39 chemotherapeutic drugs at therapeutic concentrations. The mutation frequency was assessed after induction with the SOS-inducing chemotherapeutic drugs. We then tested the ability of the three most highly inducing drugs to drive the emergence of resistant mutants of major bacterial pathogens to first-line antibiotics.RESULTS:Ten chemotherapeutic drugs activated the SOS response. Among them, eight accelerated the evolution of the major commensal E. coli, mostly through activation of the SOS response, with dacarbazine, azacitidine and streptozotocin enhancing the mutation rate 21.3-fold (P < 0.001), 101.7-fold (P = 0.01) and 1158.7-fold (P = 0.02), respectively. These three compounds also spurred the emergence of imipenem-resistant Pseudomonas aeruginosa (up to 6.21-fold; P = 0.05), ciprofloxacin-resistant Staphylococcus aureus (up to 57.72-fold; P = 0.016) and cefotaxime-resistant Enterobacteria cloacae (up to 4.57-fold; P = 0.018).CONCLUSIONS:Our results suggest that chemotherapy could accelerate evolution of the microbiota and drive the emergence of antibiotic-resistant mutants from bacterial commensals in patients. This reveals an additional level of complexity of the interactions between cancer, chemotherapy and the gut microbiota

The Quality of Anti-SARS-CoV-2 T Cell Responses Predicts the Neutralizing Antibody Titer in Convalescent Plasma Donors

International audienceConvalescent plasma therapy has been described as an attractive approach to treat critically ill patients with COVID-19 (Coronavirus disease 2019). The selection of convalescent plasma donors (CPD) is commonly based on neutralizing antibody titer. A better understanding of the quality of immune responses following COVID-19 will enable the optimization of convalescent donors' selection in convalescent plasma programs. The involvement of SARS-CoV-2 specific T cells in the induction and persistence of high affinity anti-SARS-CoV-2 neutralizing antibody is still poorly investigated. In this study, 115 CPD who presented SARS-CoV-2 and who were eligible for plasma donation were included. Comprehensive analysis of T cells together with humoral responses were performed in regards of sex, age and blood group type. High frequency of T cell responses against SARS-CoV-2 related protein such as spike glycoprotein (80.0%), nucleocapsid (NCAP) (70.4%) and membrane protein (VME1) (74.8%) were detected in CPD by e x vivo IFN-γ and TNF-α ELISpot assays. Among CPD responders, most exhibited poly-specific T cell responses (75%) defined by the ability to mount responses against at least two SARS-CoV-2 antigens. We found a positive correlation between the magnitude and the poly-specificity of anti-SARS-CoV-2 T cell responses in CPD. Notably, both the magnitude and poly-specificity of SARS-CoV-2 T cell responses were highly correlated with neutralizing antibody titer in CPD. The present study highlights that the poly-specificity and strength of SARS-CoV-2 specific T cell responses predicts neutralizing antibody titer following COVID-19. These observations show the interest to combine T cell assays and antibody titer for the selection of CPD and to a latter extend to assess COVID-19 vaccine efficacy in at-risk patients

Cisplatin-based chemoradiation decreases telomerase-specific CD4 TH1 response but increases immune suppressive cells in peripheral blood

International audienceBackground: The synergistic effect of chemoradiation (CRT) has been previously demonstrated in several cancer types. Here, we investigated the systemic immune effects of CRT in patients with lung or head and neck cancer. Materials and methods: Peripheral blood mononuclear cells were collected at baseline and 1 month after treatment from blood samples of 29 patients treated with cisplatin-based chemoradiotherapy for lung or head and neck cancer. Circulating anti-tumor Th1 response was assessed by the ELISpot assay using a mixture of human leucocyte antigen (HLA) class II restricted peptides derived from telomerase (TERT). Phenotyping of circulating immunosuppressive cells (Treg and MDSC) was performed by flow cytometry. Results: A significant increase of circulating Treg was observed in 60% of patients after CRT The mean rate of Treg was 3.1% versus 4.9% at baseline and after CRT respectively, p = 0.0015). However, there was a no significant increase of MDSC rate after CRT. In contrast, a decrease of tumor-specific Th1 response was documented in 7 out of 10 evaluated patients. We found high frequency of pre-existing tumor-specific Th1 response among patients with objective response after CRT compared to non-responders. Conclusion: Cisplatin-based CRT promotes expansion of Treg and decrease of circulating anti-tumor Th1 response in peripheral blood. The balance towards a sustained specific anti-tumor T-cell response appears to be associated with response to CRT