CD4 T cells target colorectal cancer antigens upregulated by oxaliplatin

Abstract

Immune checkpoint blockade has proven its efficacy in hypermutated subtypes of metastatic colorectal cancers (mCRC). Immunogenic potential can also be observed with conventional chemotherapies, but this property has never been explored thoroughly in CRC patients. The CRC therapeutic arsenal includes oxaliplatin, a well-characterized platinum drug already described as immunogenic. Here, we investigated the impact of the oxaliplatin-based treatment on mCRC immunopeptidome. We demonstrated that oxaliplatin-resistant CRC cell lines overexpressed telomerase reverse transcriptase (TERT), colorectalassociated-tumor antigen-1 (COA-1) and mesothelin tumor-associated antigens. We identified new HLA class-II-restricted and promiscuous peptides derived from COA-1 and mesothelin. The two naturally processed peptides COA-1 331-345 and Meso 366-380 appear to be the most immunogenic in mCRC patients. A prospective cohort of 162 mCRC patients enabled us to explore the impact of oxaliplatin exposure on the antitumor-specific immune response. Interestingly, chemotherapy-naive mCRC patients present high immune CD4 T-cell responses directed against TERT, COA-1 and mesothelin-derived peptides. These antitumor Tcell responses were maintained after 3 months of oxaliplatin-based treatment. Altogether, these findings highlight the interest of immunostimulatory agents to improve the management of chemoresistant mCRC patients. Finally, the high frequency of immune responses targeting the new immunogenic peptides derived from COA-1 and mesothelin support their use in immunomonitoring strategies. C.T. and C.V. contributed equally to this work Additional Supporting Information may be found in the online version of this article.

Anti-Telomerase CD4+ Th1 Immunity and Monocytic-Myeloid-Derived-Suppressor Cells Are Associated with Long-Term Efficacy Achieved by Docetaxel, Cisplatin, and 5-Fluorouracil (DCF) in Advanced Anal Squamous Cell Carcinoma: Translational Study of Epitopes-HPV01 and 02 Trials

“…Here, we have provided evidence that DCF chemotherapy did not hamper the level of lymphocyte counts, Treg or antigen-specific immune responses. Moreover, the high intensities and frequencies of antiviral recall of T-cell responses reported in Epitopes-HPV01 and HPV02 studies were comparable to those observed in NSCLC or colorectal cancer patients [14,15] and were not modulated by DCF chemotherapy. In contrast, our results show that DCF could decrease M-MDSC levels.…”

Telomerase and CD4 T Cell Immunity in Cancer

“…TERT is also expressed in circulating tumor cells (CTC) shed from the primary tumor [79,81,82] and is required for epithelial-mesenchymal transition (EMT) [83]. In addition, chemoresistant tumor cells can also upregulate TERT antigen [84]. Thus, it is not surprising that TERT expression levels in tumors correlate with poor prognosis in several cancer types [85,86] including lung [87] and breast [88,89] cancers.…”

“…Alternatively, chemotherapy-induced cell death could cause the release of tumor antigens and cause the activation of CD4 T cells specific for these antigens. Interestingly, an oxaliplatin-resistant colorectal cancer cell line was shown to express increased TERT levels [84]; this suggests that the input of another effective cytotoxic drug to manage chemoresistant tumor cells may facilitate anti-TERT immunity and possibly activate novel CD4 T cell clones. TERT 660-689 ALFSVLNYERARRPGLLGASVLGLDDIHRAHLA-DR p663 3 TERT 663-677 SVLNYERARRPGLLG HLA-DR p673 3 TERT 673-687 PGLLGASVLGLDDIH HLA-DR Although the mere presence of pre-existing systemic anti-TERT CD4 T cells was not sufficient to predict survival in NSCLC patients [105], greater baseline values correlated with stronger protection, both in metastatic and localized NSCLC after chemotherapy (median OS of 17 vs. 9 months in anti-TERT Th1 high vs anti-TERT Th1 low , p = 0.023) [110].…”

D-MT Prompts the Anti-Tumor Effect of Oxaliplatin by Inhibiting IDO Expression in a Mouse Model of Colon Cancer

“…It has been proven that chemotherapy could induce immunogenic cell death [34,35], thereby increasing cancer immunogenicity by promoting dendritic cell maturation and T cell in ltration in tumor tissues [36]. Furthermore, oxaliplatin could also increase T cell in ltration [37], which would favour a good prognosis for tumor patients [38]. The present results showed that oxaliplatin signi cantly increased T cell in ltration and the ratio of T cells in the spleen, indicating that oxaliplatin could play an anti-tumor effect against colon cancer.…”