Search

PURPOSE Universal cancer peptide–based vaccine (UCPVax) is a therapeutic vaccine composed of two highly selected helper peptides to induce CD4+ T helper-1 response directed against telomerase. This phase Ib/IIa trial was designed to test the safety, immunogenicity, and efficacy of a three-dose schedule in patients with metastatic non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with refractory NSCLC were assigned to receive three vaccination doses of UCPVax (0.25 mg, 0.5 mg, and 1 mg) using a Bayesian-based phase Ib followed by phase IIa de-escalating design. The primary end points were dose-limiting toxicity and immune response after three first doses of vaccine. Secondary end points were overall survival (OS) and progression-free survival at 1 year. RESULTS A total of 59 patients received UCPVax; 95% had three prior lines of systemic therapy. No dose-limiting toxicity was observed in 15 patients treated in phase Ib. The maximum tolerated dose was 1 mg. Fifty-one patients were eligible for phase IIa. The third and sixth dose of UCPVax induced specific CD4+ T helper 1 response in 56% and 87.2% of patients, respectively, with no difference between three dose levels. Twenty-one (39%) patients achieved disease control (stable disease, n = 20; complete response, n = 1). The 1-year OS was 34.1% (95% CI, 23.1 to 50.4), and the median OS was 9.7 months, with no significant difference between dose levels. The 1-year progression-free survival and the median OS were 17.2% (95% CI, 7.8 to 38.3) and 11.6 months (95% CI, 9.7 to 16.7) in immune responders ( P = .015) and 4.5% (95% CI, 0.7 to 30.8) and 5.6 months (95% CI, 2.5 to 10) in nonresponders ( P = .005), respectively. CONCLUSION UCPVax was highly immunogenic and safe and provide interesting 1-year OS rate in heavily pretreated advanced NSCLC.

Flow cytometry antibody, qPCR and Quantibrite protocol.

Effect of ANGPT2 on TAA-specific T cell responses.

Expression of TIE2 receptor by M-MDSCs.

Myeloid-derived suppressor cells (MDSC) promote immunosuppression and are a target in the field of immuno-oncology. Accumulation of MDSCs is associated with poor prognosis and resistance to immunotherapy for several cancers. Here, we describe an accumulation of a subset of circulating monocytic MDSCs (M-MDSC) overexpressing TIE2, the receptor for angiopoietin-2 (ANGPT2), in patients with non–small cell lung cancer (NSCLC). Greater numbers of circulating TIE2+ M-MDSCs were detected in patients with NSCLC compared with healthy subjects, and this accumulation correlated with ANGPT2 concentration in blood. The presence of an ANGPT2-rich environment was associated with impairment of preexisting T-cell responses against tumor-associated antigens (TAA) in patients with NSCLC. We demonstrated that ANGPT2 sensitizes TIE2+ M-MDSCs such that these cells suppress TAA-specific T cells. In patients with NSCLC, upregulation of the ANGPT2/TIE2+ M-MDSC signature in blood was associated with a poor prognosis. Our results identify the ANGPT2/TIE2+ M-MDSC axis as a participant in tumor immune evasion that should be taken into account in future cancer immunotherapy.

This file contains the patients characteristics: Supplementary table 1

This file contains the antiviral response in patients: Supplementary figure 3

This file contains the legends for the supplementary figures

The rapalogs everolimus and temsirolimus that inhibit mTOR signaling are used as antiproliferative drugs in several cancers. Here we investigated the influence of rapalogs-mediated immune modulation on their antitumor efficacy. Studies in metastatic renal cell carcinoma patients showed that everolimus promoted high expansion of FoxP3+Helios+Ki67+ regulatory CD4 T cells (Tregs). In these patients, rapalogs strongly enhanced the suppressive functions of Tregs, mainly in a contact-dependent manner. Paradoxically, a concurrent activation of spontaneous tumor-specific Th1 immunity also occurred. Furthermore, a high rate of Eomes+CD8+ T cells was detected in patients after a long-term mTOR inhibition. We found that early changes in the Tregs/antitumor Th1 balance can differentially shape the treatment efficacy. Patients presenting a shift toward decreased Tregs levels and high expansion of antitumor Th1 cells showed better clinical responses. Studies conducted in tumor-bearing mice confirmed the deleterious effect of rapalogs-induced Tregs via a mechanism involving the inhibition of antitumor T-cell immunity. Consequently, the combination of temsirolimus plus CCR4 antagonist, a receptor highly expressed on rapalogs-exposed Tregs, was more effective than monotherapy. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T-cell immunity on the clinical effectiveness of rapalogs and prompt their association with immunotherapies. Cancer Res; 76(14); 4100–12. ©2016 AACR.

This file contains the supplementary material and methods

Myeloid-derived suppressor cells (MDSC) promote immunosuppression and are a target in the field of immuno-oncology. Accumulation of MDSCs is associated with poor prognosis and resistance to immunotherapy for several cancers. Here, we describe an accumulation of a subset of circulating monocytic MDSCs (M-MDSC) overexpressing TIE2, the receptor for angiopoietin-2 (ANGPT2), in patients with non–small cell lung cancer (NSCLC). Greater numbers of circulating TIE2+ M-MDSCs were detected in patients with NSCLC compared with healthy subjects, and this accumulation correlated with ANGPT2 concentration in blood. The presence of an ANGPT2-rich environment was associated with impairment of preexisting T-cell responses against tumor-associated antigens (TAA) in patients with NSCLC. We demonstrated that ANGPT2 sensitizes TIE2+ M-MDSCs such that these cells suppress TAA-specific T cells. In patients with NSCLC, upregulation of the ANGPT2/TIE2+ M-MDSC signature in blood was associated with a poor prognosis. Our results identify the ANGPT2/TIE2+ M-MDSC axis as a participant in tumor immune evasion that should be taken into account in future cancer immunotherapy.

Plasmacytoid dendritic cells (pDCs) represent a subset of antigen-presenting cells that play an ambivalent role in cancer immunity. Here, we investigated the clinical significance of circulating pDCs and their interaction with tumor-specific T cell responses in patients with non-small cell lung cancer (NSCLC, n = 126) . The relation between intratumoral pDC signature and immune checkpoint inhibitors efficacy was also evaluated. Patients with NSCLC had low level but activated phenotype pDC compared to healthy donors. In overall population, patients with high level of pDC (pDC

Biochemical recurrence (BCR) occurs in up to 40% of prostate cancer patients after prostatectomy. In our study, we performed an immune monitoring study in 20 prostate cancer patients with BCR previously treated with metronomic cyclophosphamide (mCTX). We observed a decrease of regulatory T cells (Tregs) from 2 months and this was more pronounced after 6 months of mCTX treatment. This drop of Tregs was associated with increased level of activated HLADR+ CD45R0+ T cells in peripheral blood. Furthermore, a reactivation of Th1 polarized anti-PSA T-cell response was detected in BCR patients treated with mCTX. However, dendritic cell subsets counts and activation were not influenced by the treatment. In the clinical setting, we found that PSA level control was observed in 82% (9/11) of patients with a significant diminution of Tregs after mCTX compared to 33% (3/9) in patients without Tregs decrease. In addition, 30% (6/20) of patients previously treated with mCTX remained free for androgen deprivation therapy. In conclusion, Tregs diminution and immune activation associated with PSA level control occurred after mCTX in prostate cancer patients with BCR.

Exosomes are involved in modulating the immune system and mediating communication between cells. The aim of this study was to investigate the involvement of exosomes in psoriasis. Exosomes from patients with psoriasis were analysed by nanoparticle tracking analysis and protein expression was analysed by western blotting. The concentration of HSP70 was determined by an enzyme-linked immunosorbent assay, and concentrations of interleukin (IL)-1β, IL-2, IL-6, IL-10, IL-17A and tumour necrosis factor alpha (TNF-α) were determined by flow cytometry. Based on the severity of psoriasis, evaluated by body surface area (≤ 10% vs. > 10%), 2 groups of patients were compared (49 with mild psoriasis and 71 with moderate-to-severe psoriasis). The number (2.52×1011 ± 2.29×1010 vs. 1.79×1011 ± 1.93×1010, p = 0.19) and size (94.44 ± 22.00 nm vs. 96.87 ± 28.30 nm, p = 0.72) of exosomes and the concentration of HSP70 in the exosomes were not significantly different in the 2 groups of patients. IL-17A exosome levels were significantly higher in patients with moderate-to-severe psoriasis compared with those with mild psoriasis (p = 0.02). There were no significant differences in levels of TNF-α, IL-1, IL-2, IL-6 and IL-10. This study shows, for the first time, the presence of circulating exosomes in patients with psoriasis. These data confirm the involvement of circulating exosomes in psoriasis, in particular in moderate-to-severe psoriasis, through IL-17A-producing exosomes.

Inflammatory response in patients with COPD secondary to organic dust exposure (OD-COPD) is poorly understood. We therefore aimed to characterize inflammatory and immune profile from peripheral blood mononuclear cells (PBMC) in a group of patients with mild-to-moderate COPD secondary to organic dust exposure (OD-COPD), tobacco smoking (T-COPD), or both. We compared T, B and NK cells distribution and inflammatory (TNF-α, Il-1β, IL-6), type 1 (IFN-γ), type 2 (IL-4, IL-13) and type 3 (IL-17) immunity related cytokines at baseline, and after stimulation with LPS, flagellin and CD3/CD28 beads in all COPD groups. OD-COPD displayed significantly lower NK cells and CD8+ T cells compared with controls. After flagellin stimulation, T-COPD had significantly lower IL-13 levels than OD-COPD and controls (p 0.05) whereas IFN-γ tended to be lower in OD-COPD. All COPD groups displayed higher IL-1β and IL-17 than controls after CD3/CD28 stimulation. Inflammatory responses in OD-COPD were different from T-COPD. OD-COPD displayed higher levels of type 2 immunity related cytokines.

CD4 T cells play a key role in anticancer immunity. In this study, we investigate the clinical relevance of circulating CD4 T helper type 1 (Th1) response against telomerase (anti-TERT Th1 response) in patients with melanoma. The spontaneous anti-TERT Th1 response was detected in 54.5% (85/156) of patients with melanoma before treatment. The prevalence of this systemic response was inversely related to Breslow thickness >1 mm and American Joint Committee on Cancer stage ≥II (P = 0.001 and 0.032, respectively). In contrast to patients treated with targeted therapies, the anti-TERT Th1 immunity was associated with an objective response after immune checkpoint inhibitors treatment. Hence, 86% (18/21) of responder patients exhibited pre-existing anti-TERT Th1 versus 35% (6/19) in nonresponders (P = 0.001). This response was also associated with increased progression-free survival and overall survival in patients with melanoma treated with immune checkpoint inhibitors (P = 0.0008 and 0.012, respectively). Collectively, the presence of circulating anti-TERT Th1 response is inversely related to melanoma evolution and appears to be a predictive factor of response to immunotherapy. Our results highlight the interest in telomerase-specific CD4 Th1 response as a promising blood-based biomarker of immune checkpoint inhibitors therapy in melanoma.

mTOR pathway inhibitors such as rapalogs represent a promising tool to induce functional memory CD8 T cells. In our study, we investigated the combination of temsirolimus with anticancer vaccines. Using various designs of cancer vaccines (short and long peptides or the B subunit of Shiga toxin as an antigen delivery vector) and tumor models (melanoma, lung and colon cancer), we showed that the administration of temsirolimus efficiently decreased tumor growth and enhanced tumor-specific CD8 T-cell responses induced by vaccination. Furthermore, tumor-specific CD8 T cells induced by the bi-therapy (vaccine + temsirolimus) exhibit phenotypic characteristics of central memory (CD127+ CD62L+ ) CD8 T cells compared to vaccination alone. We demonstrated that regulatory CD4 T cells (Tregs ) expansion in vivo limits the efficacy of the bi-therapy by altering the antitumor CD8 T-cell responses. Finally, the use of a small molecule CCR4 antagonist to prevent Tregs induction considerably improved the efficacy of the bi-therapy by enhancing CD8 T cells-mediated antitumor immunity. Taken together, our study highlights the potential interest of combining cancer vaccines with drugs that promote memory CD8 T cells and inhibit Tregs .

La reponse immunitaire lymphocytaire T CD4 Th1 joue un role important dans l’immunite anti tumorale et a ete etudiee dans de nombreux cancers. Nous avons evalue la reponse immunitaire T CD4 Th1 grâce a la reponse T CD4 Th1 anti-telomerase (anti-TERT) chez des patients atteints de melanome de tous stades AJCC. La reponse anti-TERT des lymphocytes de patients atteints de melanome etait evaluee par ELISpot IFN-γ et comparee aux donnees clinico-biologiques des patients. Au total, 171 patients atteints de melanome etaient inclus et 156 d’entre eux avaient une evaluation de la reponse anti-TERT disponible. Une reponse anti-TERT etait retrouvee chez 55 % des patients. La reponse anti-TERT etait moins frequemment retrouvee lorsque les patients avaient un melanome primitif avec un indice de Breslow > a 1 mm et lorsque le stade AJCC etait ≥ II par rapport aux patients ayant un indice de Breslow ≤ 1 mm et un stade AJCC I (p = 0,010 et 0,032 respectivement). Les patients ayant une reponse anti-TERT repondaient plus frequemment a l’immunotherapie que ceux n’ayant pas de reponse anti-TERT (n = 22) (p = 0,007). Parmi les 3 parametres immunologiques mesures dans le sang des patients (MDSC, FGL1 soluble, PD-L1), le taux de MDSC etait correle de facon inverse a la presence d’une reponse anti-TERT (p = 0,008). La reponse immunitaire T CD4 Th1 anti-TERT apparait comme un facteur de bonne reponse a l’immunotherapie. Le suivi de la reponse anti-TERT represente un outil potentiel de suivi de la reponse anti-tumorale chez les patients atteints de melanome traites par immunotherapie.

Myeloid-derived suppressor cells (MDSC) promote immunosuppression and are a target in the field of immuno-oncology. Accumulation of MDSCs is associated with poor prognosis and resistance to immunotherapy for several cancers. Here, we describe an accumulation of a subset of circulating monocytic MDSCs (M-MDSC) overexpressing TIE2, the receptor for angiopoietin-2 (ANGPT2), in patients with non-small cell lung cancer (NSCLC). Greater numbers of circulating TIE2

Natural killer (NK) cells are innate effector lymphocytes widely involved in cancer immunosurveillance. In this study, we described three circulating NK cell subsets in patients with non-small cell lung cancer (NSCLC). Compared to healthy donors (HD), lower rate of the cytotoxic CD56dim CD16+ NK cells was found in NSCLC patients (76.1% vs 82.4%, P = 0.0041). In contrast, the rate of CD56bright NK cells was similar between patients and HD. We showed in NSCLC patients a higher rate of a NK cell subset with CD56dim CD16− phenotype (16.7% vs 9.9% P = 0.0001). The degranulation property and cytokines production were mainly drive by CD56dim CD16− NK cell subset in patients. Analysis of natural cytotoxicity receptors (NCRs) expression identified four distinct clusters of patients with distinct NK cell subset profiles as compared to one major cluster in HD. Notably the cluster characterized by a low circulating level of NKp46+ NK cell subsets was absent in HD. We showed that the rate of circulating NKp46+ CD56dim CD16+ NK cells influenced the patients’ survival. Indeed, the median overall survival in patients exhibiting high versus low level of this NK cell subset was 16 and 27 months respectively (P = 0.02). Finally, we demonstrated that blocking NKp46 receptor in vitro was able to restore spontaneous tumor specific T cell responses in NSCLC patients. In conclusion, this study showed a distinct distribution and phenotype of circulating NK cell subsets in NSCLC. It also supports the regulatory role of NKp46+ NK cell subset in NSCLC patients.

Background Despite the critical roles of Th1-polarised CD4+ T cells in cancer immunosurveillance, the translation of their potential to clinical use remains challenging. Here, we investigate the clinical relevance of circulating antitumor Th1 immunity in non-small cell lung cancer (NSCLC). Methods The circulating antitumor Th1 response was assessed by the ELISpot assay in 170 NSCLC patients using a mixture of HLA class II-restricted peptides from telomerase (TERT). Phenotyping of blood immune cells was performed by flow cytometry. Results TERT-reactive CD4 T-cell response was detected in 35% of NSCLC patients before any treatment. Functional analysis showed that these cells were effector memory and Th1 polarised capable to produce effector cytokines, such as IFN-γ, TNF-α and IL-2. The presence of anti-TERT Th1 response was inversely correlated with the level of exhausted PD-1+/TIM-3+CD4 T cells. The level of these two immune parameters differentially affected the survival, so that increased level of anti-TERT Th1 response and low rate of exhausted PD-1+TIM-3+CD4+ T cells were associated with a better prognosis. Conclusions Systemic anti-TERT Th1 response plays a strong antitumor protective role in NSCLC. This study underlines the potential interest of monitoring circulating antitumor Th1 response for patients’ stratification and therapy decision.

International audience; mTOR pathway inhibitors such as rapalogs represent a promising tool to induce functional memory CD8 T cells. In our study, we investigated the combination of temsirolimus with anticancer vaccines. Using various designs of cancer vaccines (short and long peptides or the B subunit of Shiga toxin as an antigen delivery vector) and tumor models (melanoma, lung and colon cancer), we showed that the administration of temsirolimus efficiently decreased tumor growth and enhanced tumor-specific CD8 T-cell responses induced by vaccination. Furthermore, tumor-specific CD8 T cells induced by the bi-therapy (vaccine + temsirolimus) exhibit phenotypic characteristics of central memory (CD127+ CD62L+ ) CD8 T cells compared to vaccination alone. We demonstrated that regulatory CD4 T cells (Tregs ) expansion in vivo limits the efficacy of the bi-therapy by altering the antitumor CD8 T-cell responses. Finally, the use of a small molecule CCR4 antagonist to prevent Tregs induction considerably improved the efficacy of the bi-therapy by enhancing CD8 T cells-mediated antitumor immunity. Taken together, our study highlights the potential interest of combining cancer vaccines with drugs that promote memory CD8 T cells and inhibit Tregs .

3044 Background: Increasing evidence highlights the crucial roles played by CD4+ Th1 cells in cancer immunity and immunotherapy (Spitzer et al., Cell 2017, Borst et al., Nat rev Immunol 2018). Here, we investigate the relevance of circulating CD4 Th1 response against shared tumor-associated antigens (TAA) in cancer patients treated by anti-PD-1 immunotherapy. Methods: A total of 46 advanced cancer patients (pts) including 32 pts with non-small cell lung cancer (NSCLC), 14 pts with melanoma, were enrolled (ITHER trial NCT02840058). Patients were treated with anti-PD-1 therapy as standard of care (26 pts with nivolumab and 20 pts with pembrolizumab). Peripheral blood mononuclear cells were collected before and after treatment at 1 and 3 months. The presence of circulating TAA-specific Th1 response was measured by IFNy ELISPOT assay using a mixture of 15mer peptides derived from telomerase (TERT) (Laheurte et al., Oncoimmunology 2016 and Br J C 2019). Results: At the baseline, the anti-TERT Th1 response was observed in 37% of pts. After anti-PD-1 therapy, de novo induction and/or amplification of pre-existing anti-TERT Th1 response was found in 26 % of pts (12/46). Whereas, a decrease of this response was documented in 15% of pts (7/46).The presence of anti-TERT Th1 response in peripheral blood during anti-PD-1 treatment was associated with a prolonged progression free-survival (PFS) as compared to the immune non responder pts (14.4 vs 2.6 months respectively, p = 0.006, HR 0.39 [0.2;0.76]). Similar observation was made for the overall survival (OS) (22.3 vs 12.3 months respectively, p = 0.04 HR 0.45 [0.21;0.96]). Notably, de novo reinvigoration of peripheral anti-TERT Th1 response after anti-PD-1 therapy was associated with a better clinical outcome as compared to the group of pts with decreased immune response after treatment (Median OS not reached vs 5.8 months). In contrast, no association with anti-PD-1 response was observed neither with circulating anti-NY-ESO-1 or with anti-viral Th1 response, concurrently measured in these patients. Conclusions: The reinvigoration of circulating CD4 Th1 against telomerase in patients treated by anti-PD-1 is associated with a better clinical outcome. These results underline the potential interest of monitoring circulating antitumor CD4 Th1 response for immune checkpoint inhibitors management.

Natural killer (NK) cells are innate effector lymphocytes widely involved in cancer immunosurveillance. In this study, we described three circulating NK cell subsets in patients with non-small cell lung cancer (NSCLC). Compared to healthy donors (HD), lower rate of the cytotoxic CD56(dim) CD16(+) NK cells was found in NSCLC patients (76.1% vs 82.4%, P = 0.0041). In contrast, the rate of CD56(bright) NK cells was similar between patients and HD. We showed in NSCLC patients a higher rate of a NK cell subset with CD56(dim) CD16(−) phenotype (16.7% vs 9.9% P = 0.0001). The degranulation property and cytokines production were mainly drive by CD56(dim) CD16(−) NK cell subset in patients. Analysis of natural cytotoxicity receptors (NCRs) expression identified four distinct clusters of patients with distinct NK cell subset profiles as compared to one major cluster in HD. Notably the cluster characterized by a low circulating level of NKp46(+) NK cell subsets was absent in HD. We showed that the rate of circulating NKp46(+) CD56(dim) CD16(+) NK cells influenced the patients’ survival. Indeed, the median overall survival in patients exhibiting high versus low level of this NK cell subset was 16 and 27 months respectively (P = 0.02). Finally, we demonstrated that blocking NKp46 receptor in vitro was able to restore spontaneous tumor specific T cell responses in NSCLC patients. In conclusion, this study showed a distinct distribution and phenotype of circulating NK cell subsets in NSCLC. It also supports the regulatory role of NKp46(+) NK cell subset in NSCLC patients.

Purpose: To investigate the immunoprevalence of SALL4-derived peptides in healthy volunteers and cancer patients. Experimental Design: A multistep approach including prediction algorithms was used to design in silico SALL4-derived peptides theoretically able to bind on common HLA-DR and HLA-A/B molecules. The presence of T-cell responses after a long term T-cell assay (28 days) against SALL4 was monitored in 14 healthy donors and the presence of T-cell responses after a short term T-cell assay (10 days) was monitored in 67 cancer patients using IFN-γ ELISPOT assay. A T-cell clone specific for the immunoprevalent A18 K-derived peptide was isolated, characterized and used as a tool to characterize the natural processing of A18 K. Results: A SALL4 specific T-cell repertoire was present in healthy donors (8/14) and cancer patients (29/67) after short term T-cell assay. We further identified two immunoprevalant SALL4-derived peptides, R18 A and A18 K, which bind MHC-class II. In parallel, an A18 K specific Th1 clone recognized monocyte derived Dendritic Cell (moDC) loaded with SALL4 containing cell lysate. The level of IFN-γ secreted by specific T-cell clone was greater in presence of moDC loaded with SALL4 containing cell lysate (49.23 ± 14.02%) than with moDC alone (18.03 ± 3.072%) (p = 0.0477) Conclusion: These results show for the first time immunogenicity of SALL4 oncogenic protein-derived peptides, especially A18 K and R18 A peptides and make them potential targets for personalized medicine. Thus, SALL4 possess major characteristics of a tumor antigen.

Despite the critical roles played by IFN-γ+ CD4 Th1 response in tumor immunity, the translation of their potential in clinic remains challenging. Here, we evaluate the clinical significance of circulating anti-tumor CD4 Th1 response in non-small cell lung cancer (NSCLC) patients. 170 naïve-treatment patients were enrolled in this immune monitoring study. The antitumor adaptive Th1 response was assessed by IFN-γ ELISPOT assay in blood lymphocytes using a mixture of eight highly promiscuous and Th1-polarized HLA class II-restricted epitopes from telomerase (TERT). The presence of anti-TERT Th1 response was detected in 59/170 patients (35%). We found an opposite link between anti-TERT Th1 and hyper exhausted T cells co-expressing PD-1+ and TIM-3+ in NSCLC patients. In contrast to hyper exhausted CD8 T cells, the presence of anti-TERT Th1 response was associated with a low rate of hyper exhausted CD4 T cells. We showed that NSCLC stage dissemination is associated with a decrease of anti-TERT Th1 response but an increase of circulating hyper exhausted PD-1+/TIM-3+ CD4 T cells. Notably, anti-telomerase Th1 response and hyper exhausted CD4 T-cells displayed opposite prognosis value in NSCLC. While high level of anti-TERT Th1 cells play a protective role, hyper-exhausted PD-1+TIM-3+ CD4 T cells negatively affect patients’ survival. By using these two circulating immune factors, we stratified patients in distinct prognostic group. Patients with anti-TERT Th1high/CD4 PD-1 TIM-3low immune profile had better overall survival than anti-TERT Th1low/CD4 PD-1 TIM-3high group (median OS : not reached versus 4 months respectively p Citation Format: Caroline Laheurte, Magalie Dosset, Dewi Vernerey, Elodie Lauret Marie Joseph, Laura Boullerot, Vincent Kaulec, Marion Jacquin, Laurie Cuche, Guillaume Eberst, Pascale Jacoulet, Virginie Westeel, Olivier Adotevi. Adaptive CD4 Th1 response against telomerase in blood counteracts T-cell exhaustion in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 575.

The rapalogs everolimus and temsirolimus that inhibit mTOR signaling are used as antiproliferative drugs in several cancers. Here we investigated the influence of rapalogs-mediated immune modulation on their antitumor efficacy. Studies in metastatic renal cell carcinoma patients showed that everolimus promoted high expansion of FoxP3+Helios+Ki67+ regulatory CD4 T cells (Tregs). In these patients, rapalogs strongly enhanced the suppressive functions of Tregs, mainly in a contact-dependent manner. Paradoxically, a concurrent activation of spontaneous tumor-specific Th1 immunity also occurred. Furthermore, a high rate of Eomes+CD8+ T cells was detected in patients after a long-term mTOR inhibition. We found that early changes in the Tregs/antitumor Th1 balance can differentially shape the treatment efficacy. Patients presenting a shift toward decreased Tregs levels and high expansion of antitumor Th1 cells showed better clinical responses. Studies conducted in tumor-bearing mice confirmed the deleterious effect of rapalogs-induced Tregs via a mechanism involving the inhibition of antitumor T-cell immunity. Consequently, the combination of temsirolimus plus CCR4 antagonist, a receptor highly expressed on rapalogs-exposed Tregs, was more effective than monotherapy. Altogether, our results describe for the first time a dual impact of host adaptive antitumor T-cell immunity on the clinical effectiveness of rapalogs and prompt their association with immunotherapies. Cancer Res; 76(14); 4100–12. ©2016 AACR.

Telomerase is a prototype-shared tumor Ag and represents an attractive target for anticancer immunotherapy. We have previously described promiscuous and immunogenic HLA-DR–restricted peptides derived from human telomerase reverse transcriptase (hTERT) and referred as universal cancer peptide (UCP). In nonsmall cell lung cancer, the presence of spontaneous UCP-specific CD4 T cell responses increases the survival of chemotherapy-responding patients. However, the precise mechanisms of hTERT’s uptake, processing, and presentation on MHC-II molecules to stimulate CD4 T cells are poorly understood. In this work, by using well-characterized UCP-specific CD4 T cell clones, we showed that hTERT processing and presentation on MHC-II involve both classical endolysosomal and nonclassical cytosolic pathways. Furthermore, to our knowledge, we demonstrated for the first time that hTERT’s internalization by dendritic cells requires its interaction with surface heparan sulfate proteoglycans. Altogether, our findings provide a novel mechanism of tumor-specific CD4 T cell activation and will be useful for the development of novel cancer immunotherapies that harness CD4 T cells.

L’efficacite des immunotherapies antitumorales a recemment connu un tournant dans l’histoire du traitement des cancers. En effet, l’utilisation d’anticorps monoclonaux ciblant les recepteurs tels que PD-1, PDL1 ou CTLA-4, ont permis d’obtenir des reponses cliniques prometteuses et durables dans differents types de cancers humains. Cependant, ces immunotherapies ne fonctionnent que chez environ 20–40 % des patients selon les cancers. Afin d’ameliorer l’efficacite de ces immunotherapies innovantes, nous proposons de les combiner avec la radio-chimiotherapie. L’action synergique de la combinaison radio-chimiotherapie concomitante (RTCTc) est bien connue en cancerologie, notamment dans le cancer du poumon. Cependant, contrairement a la monotherapie, l’immunomodulation, induite par la combinaison RTCTc est peu connue. Dans ce projet, nous avons analyse chez l’Homme et dans differents modeles tumoraux murins la modulation des reponses T antitumorales induites par la RTCTc et etudie les mecanismes de cette immunomodulation. Chez la souris, nos premiers resultats montrent que la RTCTc augmente a la fois l’infiltration tumorale de cellules immunosuppressives telles que les Treg et les MDSC et augmente l’infiltration de LT CD8 specifiques. Cependant, ces LT CD8 sont peu fonctionnels (incapacite de produire l’IFNg). L’elimination conditionnelle des Treg ameliore nettement l’efficacite antitumorale de la RTCTc mais les LT CD8 restent peu fonctionnels. Leur absence de fonctionnalite est probablement liee a la surexpression des recepteurs inhibiteurs PD1+ TIM3+ et de PDL1 par les cellules tumorales observee apres RTCTc. Des resultats preliminaires obtenus chez des patients atteints de cancer bronchique traites par RTCTc confirment l’augmentation des taux de Treg et MDSC circulants. De plus, nous avons observe une perte des reponses Th1 specifiques de tumeur dans le sang apres RTCTc, alors que les reponses antivirales de ces patients restent conservees. Les immunotherapies telles que les anticorps anti-PD1 ou anti-PDL1 sont actuellement prescrites dans les cancers bronchiques et fonctionnent en reactivant les reponses immunitaires antitumorales du patient. Il existe donc un rationnel solide pour combiner ces immunotherapies nouvelles avec la RTCTc concomitante. La comprehension de l’immunomodulation induite par la RTCTc permettrait de developper de nouvelles combinaisons therapeutiques synergiques et efficaces pour une majorite de patients actuellement refractaires aux therapies actuelles.