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

Abstract

Purpose: Innate immunity is an indispensable arm of tumor immune surveillance, and the liver is an organ with a 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 patients with HCC were evaluated by both flow cytometry (FCM) and in vitro bioassays. Transcriptomic analysis of MAIT cells was also performed. Prognostic significance of tumor-infiltrating MAIT cells was validated in four independent cohorts of patients with HCC. Results: Despite their fewer densities in HCC tumor than normal liver, MAIT cells were significantly enriched in the HCC microenvironment compared with other mucosaassociated organs. Tumor-derived MAIT cells displayed a typical CCR7 À CD45RA À CD45RO þ CD95 þ effector memory phenotype with lower costimulatory and effector capabilities. Tumor-educated MAIT cells significantly upregulated inhibitory molecules like PD-1, CTLA-4, TIM-3, secreted significantly less IFNg and IL17, and produced minimal granzyme B and perforin while shifting to produce tumor-promoting cytokines like IL8. Transcriptome sequencing confirmed that tumor-derived MAIT cells were reprogrammed toward a tumor-promoting direction by downregulating genes enriched in pathways of cytokine secretion and cytolysis effector function like NFKB1 and STAT5B and by upregulating genes like IL8, 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 IHC 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. See related commentary by Carbone, p. 3199

Single-Cell Mass Cytometry on Peripheral Blood Identifies Immune Cell Subsets Associated with Primary Biliary Cholangitis

“…Moreover, the abundance of this metacluster was reduced even further in cirrhotic compared to non-cirrhotic PBC patients. This finding is consistent with studies of other chronic liver diseases, including hepatitis B viral infection 26 and hepatocellular carcinoma 27 , which implicate exhaustion and loss of MAIT cells with worsening liver damage. Considering the apparent importance of these cells in PBC, our future efforts should include additional MAIT-specific markers such as the MAITinvariant T cell receptor (Vα7.2).…”

Mucosal-associated invariant T cells and disease

“…Recent studies have investigated the role of MAIT cells in cancer, and the observations reported are similar to those made in autoimmune and inflammatory diseases (TaBles 3,4). Circulating MAIT cell frequency is decreased in patients with colorectal cancer (CRC) [134][135][136] , hepatocellular carcinoma (HCC) 137 and lung cancer 136 . MAIT cells accumulate in tumour tissues from patients with colon adenocarcinomas 138 and CRC, particularly in those with advanced CRC [134][135][136] , and in hepatic metastatic lesions in patients with CRC 139 .…”

“…As we observed in immunemediated diseases, this could reflect increased apoptosis of MAIT cells, possibly as a result of their chronic activation. Indeed, in patients with HCC, tumour-infiltrating MAIT cells had an exhausted phenotype, with high PD-1, CTLA4 and TIM3 expression, and produced less IFNγ and IL-17 than MAIT cells from healthy donors 137 . Similarly, MAIT cells from colonic adenocarcinomas produced less IFNγ than MAIT cells from healthy colons 138 , suggesting that tumour-infiltrating MAIT cells might be altered due to tumour microenvironmental factors.…”

MAIT Cells Come to the Rescue in Cancer Immunotherapy?

“…In hepatocellular carcinoma (HCC) patients, peripheral blood MAIT cells are numerically and functionally depleted [86]. Similar discoveries were made in terms of several chronic inflammatory conditions that are associated with an increased risk of malignant transformation in the liver, namely hepatitis C virus (HCV) infection [87], primary biliary cholangitis [88], and alcoholic and non-alcoholic fatty liver disease [89].…”