Tissue-Resident Cytotoxic γδT Cells in Anti-tumor Immunity 2258876

Abstract

Abstract Introduction Tissue-resident αβT cells are well-documented to play a critical role in controlling solid tumors. In contrast, the characteristics and function of tissue-resident γδT cells remain poorly understood. γδ;T cells are a heterogeneous T cell population characterized by phenotypic diversity and functional variability in response to infection and cancer. The IFN-γ-IL-17 dichotomy among γδT cells is particularly related to their effector functions in cancer. Methods To investigate the heterogeneity of tumor-infiltrating γδT cells, we performed single-cell RNA sequencing (scRNA-seq) on liver CD45+TCRγδ+CD3+ cells isolated from hepatocellular carcinoma (HCC)-bearing mice. A distinct cytotoxic γδT cell population was identified. Using a parabiosis model, we confirmed that this cytotoxic γδT cell subset represents liver-resident cells. Both in vitro cytotoxicity assays and in vivo adoptive cell transfer experiments demonstrated that these liver-resident cytotoxic γδT cells effectively controlled tumor growth. Results In this study, we report a subset of tissue-resident γδT cell population which possess potent cytotoxic activity. These cytotoxic γδT cells are present across various organs but particularly enriched in the liver. These cells resist the immunosuppressive tumor microenvironment (TME), which distinguish them from conventional γδT cells and exhibit robust anti-tumor activity both in vitro and in vivo. Notably, the cytotoxicity of this tissue-resident γδT cells is independent of IFN-γ. Conclusion These findings offer valuable insights into the subset of tissue-resident cytotoxic γδT cells and their therapeutic potential in cancer immunotherapy. Funding Source n/a Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)