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Role of kynurenine in promoting the generation of exhausted CD8⁺ T cells in colorectal cancer.

ABSTRACT: Although blocking programmed cell death protein 1 (PD-1) has emerged as a standard treatment for metastatic colorectal cancer (CRC), a vast majority of CRC patients still respond poorly to anti-PD-1 immunotherapy. In this study, we showed that the levels of indoleamine 2,3-dioxygenase 1 (IDO1) and its catabolite kynurenine (Kyn) were higher in late stages (stages III and IV) than in early stages (stages I and II) of CRC patients. We found that Kyn could induce the expression of immune checkpoints and exhaustion markers in CD8⁺ tumor-infiltrating T cells. Knockdown of IDO1 expression using small hairpin RNAs (shRNAs) in the MC38 and CT26 colorectal cell lines led downregulation of Kyn expression and activation of CD8⁺ T cells in MC38- or CT26-bearing mice. Subsequent mechanistic study revealed significantly reduced thymocyte selection-associated HMG box (TOX) mRNA levels in CD8⁺ tumor-infiltrating T cells isolated from IDO1 knockdown MC38-Scr- and CT26-bearing mice. Kyn-induced CD8⁺ T cell exhaustion was reversed by knockdown of TOX expression. Finally, the application of the well-known IDO1 inhibitors 1MT or NLG919 substantially improved the therapeutic effect of CRC in vivo and restored CD8⁺ tumor-infiltrating T cells anti-tumor activity. This improvement was further enhanced by an anti-PD-1 combined therapy. In conclusion, our study revealed a novel mechanism underlying the metabolic factors found in tumor microenvironment which could induce CD8⁺ T cells exhaustion. Our findings provided a new strategy of restoring the antitumor activity of CD8⁺ T cells through combined targeting of the IDO1/Kyn and PD-1/PD-L1 pathways in patients with CRC.

SUBMITTER: Wu D

PROVIDER: S-EPMC8014392 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionDespite recent advances in immunotherapy for hepatocellular carcinoma (HCC), the overall modest response rate underscores the need for a better understanding of the tumor microenvironment (TME) of HCC. We have previously shown that CD38 is widely expressed on tumor-infiltrating leukocytes (TILs), predominantly on CD3+ T cells and monocytes. However, its specific role in the HCC TME remains unclear.MethodsIn this current study, we used cytometry time-of-flight (CyTOF), bulk RNA sequencing on sorted T cells, and single-cell RNA (scRNA) sequencing to interrogate expression of CD38 and its correlation with T cell exhaustion in HCC samples. We also employed multiplex immunohistochemistry (mIHC) for validating our findings.ResultsFrom CyTOF analysis, we compared the immune composition of CD38-expressing leukocytes in TILs, non-tumor tissue-infiltrating leukocytes (NIL), and peripheral blood mononuclear cells (PBMC). We identified CD8+ T cells as the dominant CD38-expressing TILs and found that CD38 expression was significantly higher in CD8+ TRM in TILs than in NILs. Furthermore, through transcriptomic analysis on sorted CD8+ TRM from HCC tumors, we observed a higher expression of CD38 along with T cell exhaustion genes, including PDCD1 and CTLA4, compared to the circulating memory CD8 T cells from PBMC. This was validated by scRNA sequencing that revealed co-expression of CD38 with PDCD1, CTLA4, and ITGAE (CD103) in T cells from HCC tumors. The protein co-expression of CD38 and PD-1 on CD8+ T cells was further demonstrated by mIHC on HCC FFPE tissues, marking CD38 as a T cell co-exhaustion marker in HCC. Lastly, the higher proportions of CD38+PD-1+ CD8+ T cells and CD38+PD-1+ TRM were significantly associated with the higher histopathological grades of HCC, indicating its role in the aggressiveness of the disease.ConclusionTaken together, the concurrent expression of CD38 with exhaustion markers on CD8+ TRM underpins its role as a key marker of T cell exhaustion and a potential therapeutic target for restoring cytotoxic T cell function in HCC.

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Role of kynurenine in promoting the generation of exhausted CD8⁺ T cells in colorectal cancer.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Role of kynurenine in promoting the generation of exhausted CD8+ T cells in colorectal cancer.

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OmicsDI is part of the ELIXIR infrastructure

Tweets

Role of kynurenine in promoting the generation of exhausted CD8⁺ T cells in colorectal cancer.