Oral Presentation CD1-MR1 2024

The anti-tumour effector function of mucosal-associated invariant T cells is impaired by fatty acids and aberrant lipid metabolism (#81)

Sebastian Deschler 1 , Lukas Ramsauer 2 , Philippa Meiser 2 , Robin P Schenk 1 , Junika Pohl-Topcu 1 , Juliane Kager 1 , Sophia Erlacher 1 , Joseph Zink 1 , Karyna Pistrenko 1 , Julius Weber 1 , Fabian Geisler 1 , Gabriela M Wiedemann 1 , Karin Kleigrewe 3 , Carolin Mogler 4 , Jan P Böttcher 2 , Percy A Knolle 2 , Roland M Schmid 1 , Katrin Böttcher 1
  1. Department of Internal Medicine II, University Hospital rechts der Isar, Technical University Munich, Munich, Germany
  2. Institute of Molecular Immunology and Experimental Oncology, University Hospital Rechts der Isar, Technical University Munich, Munich, Germany
  3. Bavarian Center for Biomolecular Mass Spectrometry, Technical University Munich, Munich, Germany
  4. Institute of Pathology, Technical University Munich, Munich, Germany

Mucosal-associated invariant T (MAIT) cells, the most abundant innate-like T cell population in the liver1, harbour anti-cancer potential. However, their effector function is impaired in hepatocellular carcinoma2 (HCC), a frequent cause for cancer-related deaths worldwide3. Here, we aim to decipher the mechanism by which MAIT cell effector function is impaired in the liver microenvironment. Therefore, we analysed how metabolic changes in non-alcoholic fatty liver disease (NAFLD), a common precondition for HCC development3, affect the phenotype and effector function of MAIT cells. 

MAIT cells from peripheral blood of NAFLD patients or healthy controls were stimulated in vitro, and MAIT cells from healthy controls were challenged with fatty acids during restimulation. MAIT cell phenotype and function was analysed by multi-colour flow cytometry, metabolism was investigated by metabolic flux analysis and gene expression by RNA sequencing.

We show that NAFLD MAIT cells express significantly higher levels of activation markers and effector cytokines ex vivo, suggesting MAIT cell activation in NAFLD in vivo. Activation of MAIT cells in NAFLD was associated with higher levels of glycolysis ex vivo. However, upon in vitro restimulation, these activated MAIT cells were dysfunctional and failed to produce effector cytokines, such as IFN gamma, Granzyme B and TNF alpha. Culture with distinct fatty acid species characteristic of the NAFLD microenvironment, however, impaired expression of effector cytokines by MAIT cells and abrogated their HCC cell killing capacity. Mechanistically, these effects were mediated by corrupted mitochondrial function and aberrant lipid metabolism and could be rescued by treatment with redox regulators.

Our data show that MAIT cells are highly activated but dysfunctional in NAFLD and suggest that impairment of MAIT cell anti-tumour effector function is mediated by metabolic signals in the hepatic microenvironment. Our data provide novel mechanistic insight that could be harnessed to improve the anti-cancer function of MAIT cells.

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