Mucosal-associated invariant T (MAIT) cells possess direct anti-tumour potential, but are rendered dysfunctional within the tumour microenvironment in HCC

Hepatocellular carcinoma (HCC) is a major cause of cancer death worldwide. Innate-like mucosal-associated invariant T (MAIT) cells are protective against HCC in murine models but often dysfunctional in human HCC patients for reasons that are incompletely understood. Here, we aim to unravel molecular mechanisms of MAIT cell cytotoxicity and dysfunction within the tumour microenvironment in HCC in human patients. MAIT cells were isolated from human liver tissue and peripheral blood. Primary MAIT cells were co-cultured with various HCC cell lines in vitro and MAIT cell phenotype and function was analysed by multi-colour flow cytometry. MAIT cell cytotoxicity was tested by real-time viability assays using xCelligence. We uncover a so far unrecognised direct cytotoxic capacity of human MAIT cells against HCC cells employing an in vitro co-culture system. Mechanistically, MAIT cell cytotoxicity is dependent on signalling via death receptors of the tumor necrosis factor superfamily as well as effector cytokines secreted by MAIT cells. In HCC patients, MAIT cells are systemically reduced in frequency and excluded from HCC tumour tissue. Importantly, tumour-educated MAIT cells express a dysfunctional phenotype, which is induced by HCC cells in a cell contact-dependent manner. Importantly, MAIT anti-tumour capacity could be enhanced by targeting the death receptor – cytokine axis we have identified. Our results demonstrate a direct cytotoxic capacity of MAIT cells against HCC cells and suggest that enhancing the anti-tumour potential of MAIT cells could be harnessed to improve immunotherapeutic strategies against HCC. Publication History Article published online: 20 January 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany