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Telomerase reverse transcriptase (TERT) is a conserved self-tumor antigen overexpressed in ∼85% of tumor cells and is immunogenic in cancer patients. The effect of TERT expression on the regulation of intratumor adaptive immunity has not yet been investigated. We used RNA sequencing data from The Cancer Genome Atlas (TCGA) in 11 solid tumor types to investigate potential interactions between TERT expression, and B and T cell infiltrate in the tumor microenvironment. We found a positive correlation between TERT expression, B and T cells in four cancer types with the strongest association in head and neck squamous cell carcinoma (HSNCC). In HNSCC a Bhigh/TERThigh signature was associated with improved progression-free survival (PFS) (P = 0.0048). This effect was independent of HPV status and not shared in comparable analysis by other conserved tumor antigens (NYESO1, MUC1, MAGE, and CEA). Bhigh/TERThigh HNSCC tumors also harbored evidence of tertiary lymphoid structure (TLS) such as signatures for germinal center (GC) and switched memory B cells, central memory CD4 and effector memory CD8 T cells. Bhigh/TERThigh HNSCC tumors also showed an up-regulation of genes and pathways related to B and T cell activation, proliferation, migration, and cytotoxicity, while factors associated with immunosuppression and cancer cell invasiveness were down-regulated. In summary, our study uncovers a new association between high TERT expression and high B cell infiltrate in HNSCC, suggesting a potential benefit from therapeutic strategies that invigorate intratumor TERT-mediated T-B cooperation.

The tumor-immune interface has surged to primary relevance in an effort to understand the hurdles facing immune surveillance and cancer immunotherapy. Reports over the past decades have indicated a role for the unfolded protein response (UPR) in modulating not only tumor cell fitness and drug resistance, but also local immunity, with emphasis on the phenotype and altered function of immune cells such as myeloid cells and T cells. Emerging evidence also suggests that aneuploidy correlates with local immune dysregulation. Recently, we reported that the UPR serves as a link between aneuploidy and immune cell dysregulation in a cell nonautonomous way. These new findings add considerable complexity to the organization of the tumor microenvironment (TME) and the origin of its altered function. In this review, we summarize these data and also discuss the role of aneuploidy as a negative regulator of local immunity.

Aneuploidy is a chromosomal abnormality associated with poor prognosis in many cancer types. Here, we tested the hypothesis that the unfolded protein response (UPR) mechanistically links aneuploidy and local immune dysregulation. Using a single somatic copy number alteration (SCNA) score inclusive of whole-chromosome, chromosome arm, and focal alterations in a pan-cancer analysis of 9,375 samples in The Cancer Genome Atlas (TCGA) database, we found an inverse correlation with a cytotoxicity (CYT) score across disease stages. Co-expression patterns of UPR genes changed substantially between SCNAlow and SCNAhigh groups. Pathway activity scores showed increased activity of multiple branches of the UPR in response to aneuploidy. The PERK branch showed the strongest association with a reduced CYT score. The conditioned medium of aneuploid cells transmitted XBP1 splicing and caused IL-6 and arginase 1 transcription in receiver bone marrow-derived macrophages and markedly diminished the production of IFN-γ and granzyme B in activated human T cells. We propose the UPR as a mechanistic link between aneuploidy and immune dysregulation in the tumor microenvironment.

Telomerase reverse transcriptase (TERT) is a conserved self-tumor antigen which is overexpressed in most tumors and plays a critical role in tumor formation and progression. As such, TERT is an antigen of great relevance to develop widely applicable immunotherapies. CD4 T cells play a major role in the anti-cancer response alone or with other effector cells such as CD8 T cells and NK cells. To date, efforts have been made to identify TERT peptides capable of stimulating CD4 T cells that are also able to bind diverse MHC-II alleles to ease immune status monitoring and immunotherapies. Here, we review the current status of TERT biology, TERT/MHC-II immunobiology, and past and current vaccine clinical trials. We propose that monitoring CD4 T cell immunity against TERT is a simple and direct way to assess immune surveillance in cancer patients and a new way to predict the response to immune checkpoint inhibitors (ICPi). Finally, we present the initial results of a systematic discovery of TERT peptides able to bind the most common HLA Class II alleles worldwide and show that the repertoire of MHC-II TERT peptides is wider than currently appreciated.

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. [ABSTRACT FROM AUTHOR]

Autophagy, a catabolic mechanism that involves degradation of cellular components, is essential for cell homeostasis. Although autophagy favours the lineage stability of regulatory T cells, the contribution of autophagy to the differentiation of effector CD4 T cells remains unclear. Here we show that autophagy selectively represses T helper 9 (TH9) cell differentiation. CD4 T cells lacking Atg3 or Atg5 have increased interleukin-9 (IL-9) expression upon differentiation into TH9 cells relative to Atg3- or Atg5-expressing control cells. In addition, the TH9 cell transcription factor, PU.1, undergoes K63 ubiquitination and degradation through p62-dependent selective autophagy. Finally, the blockade of autophagy enhances TH9 cell anticancer functions in vivo, and mice with T cell-specific deletion of Atg5 have reduced tumour outgrowth in an IL-9-dependent manner. Overall, our findings reveal an unexpected function of autophagy in the modulation of TH9 cell differentiation and antitumour activity, and prompt potential autophagy-dependent modulations of TH9 activity for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Cumulative evidence supports that CD4+Th1 cells play a key role in antitumor immunity. We previously reported the presence of spontaneous HLA-DR-restricted CD4+Th1 responses against telomerase reverse transcriptase (TERT) in various cancers by using promiscuous HLA-DR epitopes. Here, we described novel highly immunogenic HLA-DP4-binding epitopes from TERT named TERT541–555, TERT573–587, TERT613–627and TERT911–925and addressed the question about the immunoprevalence and magnitude of the naturally occurring antitumor CD4+T cell responses restricted by HLA-DP4 or HLA-DR, the two most common HLA class II. Direct comparative study of spontaneous anti-TERT CD4+T cell responses in a cohort of 87 lung cancer patients showed that HLA-DP4 and HLA-DR sustained specific Th1 responses in 10.1% and 25.2% of cancer patients respectively (p= 0.01). The magnitude of the HLA-DR-restricted responses was two to three times significantly higher than HLA-DP one (p= 0.005). Similar results were found in other cancers such as melanoma, breast cancer, renal cell carcinoma and colon cancer. Thus, our results describe for the first time in a large cohort of cancer patients a high immunoprevalence of HLA-DR-restricted spontaneous anti-TERT Th1 immunity compared to HLA-DP restriction. These results provide a new tool for comprehensive monitoring of antitumor CD4+Th1 response in various cancers. [ABSTRACT FROM AUTHOR]

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.

Background: Chemotherapy is currently evaluated in order to enhance the efficacy of immune checkpoint blockade (ICB) therapy in colorectal cancer. However, the mechanisms by which these drugs could synergize with ICB remains unclear. The impact of chemotherapy on the PD-1/PD-L1 pathway and the resulting anticancer immune responses was assessed in two mouse models of colorectal cancer and validated in tumor samples from metastatic colorectal cancer patients that received neoadjuvant treatment. We demonstrated that 5-Fluorouracil plus Oxaliplatin (Folfox) drove complete tumor cure in mice when combined to anti-PD-1 treatment, while each monotherapy failed. This synergistic effect relies on the ability of Folfox to induce tumor infiltration by activated PD-1 + CD8 T cells in a T-bet dependent manner. This effect was concomitantly associated to the expression of PD-L1 on tumor cells driven by IFN-γ secreted by PD-1+ CD8 T cells, indicating that Folfox triggers tumor adaptive immune resistance. Finally, we observed an induction of PD-L1 expression and high CD8 T cell infiltration in the tumor microenvironment of colorectal cancer patients treated by Folfox regimen. Our study delineates a molecular pathway involved in Folfox-induced adaptive immune resistance in colorectal cancer. The results strongly support the use of immune checkpoint blockade therapy in combination with chemotherapies like Folfox.

Autophagy, a catabolic mechanism that involves degradation of cellular components, is essential for cell homeostasis. Although autophagy favours the lineage stability of regulatory T cells, the contribution of autophagy to the differentiation of effector CD4 T cells remains unclear. Here we show that autophagy selectively represses T helper 9 (T H 9) cell differentiation. CD4 T cells lacking Atg3 or Atg5 have increased interleukin-9 (IL-9) expression upon differentiation into T H 9 cells relative to Atg3- or Atg5-expressing control cells. In addition, the T H 9 cell transcription factor, PU.1, undergoes K63 ubiquitination and degradation through p62-dependent selective autophagy. Finally, the blockade of autophagy enhances T H 9 cell anticancer functions in vivo, and mice with T cell-specific deletion of Atg5 have reduced tumour outgrowth in an IL-9-dependent manner. Overall, our findings reveal an unexpected function of autophagy in the modulation of T H 9 cell differentiation and antitumour activity, and prompt potential autophagy-dependent modulations of T H 9 activity for cancer immunotherapy.Autophagy is a cellular process for recycling cell constituents, and is essential for T cell activation, but its function in T cell polarization is still unclear. Here the authors show that autophagy induces the degradation of transcription factor PU.1 to negatively modulate T H 9 homeostasis and antitumour immunity.