Poster Presentation CD1-MR1 Workshop 2025

MAIT cells possess direct cytotoxic potential against liver cancer, but are rendered dysfunctional within the tumour microenvironment (#154)

Junika Pohl-Topcu 1 , Enric Redondo Monte 1 , Sebastian Deschler 1 , Sophia Erlacher 1 , Joseph Zink 1 , Anna Marie Pedde 2 , Anna Hirschberger 2 , Hanno Nieß 3 , Melanie Laschinger 4 , Daniel Hartmann 4 5 , Norbert Hüser 4 , Percy A. Knolle 2 , Roland M. Schmid 1 , Katrin Böttcher 1 6
  1. Clinical Department of Internal Medicine II, School of Medicine and Health, TUM University Hospital, Munich, Germany
  2. Institute for Molecular Immunology, School of Medicine and Health, TUM University Hospital, Munich, Germany
  3. Department of General, Visceral- and Transplant Surgery, LMU Hospital, Munich, Germany
  4. Clinical Department for Surgery, School of Medicine and Health, TUM University Hospital, Munich, Germany
  5. Department of Surgery, University Hospital Tübingen, M3 Research Center, Tübingen, Germany
  6. Department of Internal Medicine I, M3 Research Center, University Hospital Tübingen, Tübingen, Germany

MAIT cells are protective against liver cancer, a major cause of cancer death worldwide, in murine models. However, in human cancer patients, MAIT cells are rendered dysfunctional for unclear reasons. Here, we aim to unravel the molecular mechanisms of MAIT cell cytotoxicity and dysfunction within the tumour microenvironment in human cancer patients with the aim to identify novel, MAIT cell-targeted anti-cancer strategies.

MAIT cells were isolated from human liver tissue and peripheral blood. Primary MAIT cells were co-cultured with various liver cancer cell lines and primary human hepatocytes in vitro. MAIT cell phenotype and function were analysed by multi-colour flow cytometry. MAIT cell cytotoxicity was tested by real-time viability assays using xCelligence.

Here, we uncover a so far unrecognised, direct cytotoxic capacity of human MAIT cells against hepatocellular carcinoma (HCC) cells employing an in vitro co-culture system. Importantly, activated MAIT cells selectively killed HCC cells but not primary hepatocytes. T cell receptor-mediated activation of MAIT cells was indispensable for MAIT cell cytotoxicity, which was, however, independent of MR1 signalling. Mechanistically, MAIT cell cytotoxicity required signalling via death receptors of the tumour necrosis factor superfamily and effector cytokines secreted by MAIT cells. In human HCC patients, MAIT cells are systemically reduced in frequency and excluded from HCC tumour tissue. Moreover, tumour-educated MAIT cells express a dysfunctional phenotype, which was directly induced by HCC cells in a cell contact-dependent manner, or by metabolites in the tumour microenvironment. Importantly, such MAIT dysfunction resulted in poorer clinical outcomes for patients with HCC. MAIT cell cytotoxicity could be enhanced by targeting the death receptor – cytokine axis we have identified.

Our results demonstrate a novel, direct cytotoxic capacity of human MAIT cells against HCC cells, which is dependent on death receptor signalling and MAIT cell cytokines. These findings suggest that enhancing the anti-tumour potential of MAIT cells could be harnessed to improve current immunotherapeutic strategies.