The anti-tumour effector function of mucosal-associated invariant T cells against hepatocellular carcinoma is impaired by fatty acids and aberrant lipid metabolism

Mucosal-associated invariant T (MAIT) cells, the most abundant innate-like T cell population in the liver, harbour anti-cancer potential. However, their effector function is impaired in hepatocellular carcinoma (HCC) for reasons that are incompletely understood. Here, we aim to decipher the mechanism by which MAIT cell effector function is impaired in metabolic dysfunction-associated steatotic liver disease (MASLD), a common precondition for HCC development.

MAIT cells from peripheral blood of MASLD patients or healthy controls were stimulated ex vivo, and MAIT cells from healthy controls were challenged with fatty acids during stimulation. 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 MASLD MAIT cells express higher levels of activation markers and effector cytokines ex vivo, suggesting MAIT cell activation in MASLD in vivo. However, upon ex vivo restimulation, these activated MAIT cells were dysfunctional and failed to produce effector cytokines. Notably, culture with distinct fatty acid species characteristic of the MASLD microenvironment and accumulating in our MASLD patient cohort, impaired expression of effector cytokines by MAIT cells and abrogated their HCC cell killing capacity. Mechanistically, these effects were mediated by corrupted mitochondrial function, oxidative stress and aberrant lipid metabolism and could be rescued by treatment with redox regulators.

Taken together, we show that impairment of MAIT cell anti-tumour effector function against HCC is mediated by metabolic signals in the hepatic microenvironment in MASLD patients that induce oxidative stress and corrupt MAIT cell metabolism.

Publication History

Article published online:
20 January 2025