Activated and Exhausted MAIT Cells Foster Disease Progression and Indicate Poor Outcome in Hepatocellular Carcinoma

Purpose: Innate immunity is an indispensable arm of tumor immune surveillance, and the liver is an organ with predominance of innate immunity, where mucosal-associated invariant T (MAIT) cells are enriched. However, little is known about the phenotype, functions and immunomodulatory role of MAIT cells in hepatocellular carcinoma (HCC). Experimental Design: The distribution, phenotype, and function of MAIT cells in HCC patients were evaluated by both FCM and in vitro bio-assays. Transcriptomic analysis of MAIT cells was also performed. Prognostic significance of tumor-infiltrating MAIT cells was validated in four independent cohorts of HCC patients. Results: Despite their fewer densities in HCC tumor than normal liver, MAIT cells were significantly enriched in HCC microenvironment compared to other mucosa-associated organs. Tumor-derived MAIT cells displayed a typical CCR7-CD45RA-CD45RO+CD95+ effector memory phenotype with lower co-stimulatory and effector capabilities. Tumor-educated MAIT cells significantly upregulated inhibitory molecules like PD-1, CTLA-4, TIM-3, and secreted significantly less IFN- and IL-17, and produced minimal granzyme B and perforin, while shifted to produce tumor-promoting cytokines like IL-8. Transcriptome sequencing confirmed that tumor-derived MAIT cells were reprogrammed toward a tumor-promoting direction, by down-regulating genes enriched in pathways of cytokine secreting and cytolysis effector function, like NFKB1 and STAT5B, and by up-regulating genes like IL-8, CXCL12 and HAVCR2 (TIM-3). High infiltration of MAIT cells in HCC significantly correlated with an unfavorable clinical outcome, revealed by FCM, qRT-PCR and multiplex immunohistochemistry analyses respectively. Conclusions: HCC-infiltrating MAIT cells were functionally impaired and even reprogrammed to shift away from antitumor immunity and toward a tumor-promoting direction.

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