CD38 marks the exhausted CD8+ tissue-resident memory T cells in hepatocellular carcinoma

作者：Marie J. Y. Reolo, Masayuki Otsuka, Justine Jia Wen Seow, Joycelyn Jie Xin Lee, Yun Hua Lee, Phuong H. D. Nguyen, Chun Jye Lim, Martin Wasser, Camillus Jian Hui Chua, Tony Kiat Hon Lim, Wei Qiang Leow, Alexander Yaw Fui Chung, Brian K. P. Goh, Pierce K. H. Chow, Ramanuj DasGupta, Joe Poh-Sheng Yeong, Valerie Chew · 发表于：Frontiers in Immunology · 年份：2023 · 被引用次数：16 · 研究领域：Immune Cell Function and Interaction、T-cell and B-cell Immunology、Cancer Immunotherapy and Biomarkers

Introduction Despite 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. Methods In 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. Results From 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-expressi...