Abstract

Mucosa-associated invariant T (MAIT) cells are unconventional, innate-like T lymphocytes that recognize vitamin B metabolites of microbial origin among other antigens displayed by the monomorphic molecule MHC class I-related protein 1 (MR1). Abundant in human tissues, reactive to local inflammatory cues, and endowed with immunomodulatory and cytolytic functions, MAIT cells are likely to play key roles in human malignancies. They accumulate in various tumor microenvironments (TMEs) where they often lose some of their functional capacities. However, the potential roles of MAIT cells in anticancer immunity or cancer progression and their significance in shaping clinical outcomes remain largely unknown. In this study, we analyzed publicly available bulk and single-cell tumor transcriptomic datasets to investigate the tissue distribution, phenotype, and prognostic significance of MAIT cells across several human cancers. We found that expanded MAIT cell clonotypes were often shared between the blood, tumor tissue and adjacent healthy tissue of patients with colorectal, hepatocellular, and non-small cell lung carcinomas. Gene expression comparisons between tumor-infiltrating and healthy tissue MAIT cells revealed the presence of activation and/or exhaustion programs within the TMEs of primary hepatocellular and colorectal carcinomas. Interestingly, in basal and squamous cell carcinomas of the skin, programmed cell death-1 (PD-1) blockade upregulated the expression of several effector genes in tumor-infiltrating MAIT cells. We derived a signature comprising stable and specific MAIT cell gene markers across several tissue compartments and cancer types. By applying this signature to estimate MAIT cell abundance in pan-cancer gene expression data, we demonstrate that a heavier intratumoral MAIT cell presence is positively correlated with a favorable prognosis in esophageal carcinoma but predicts poor overall survival in colorectal and squamous cell lung carcinomas. Finally, in colorectal carcinoma and four other cancer types, we found a positive correlation between MR1 expression and estimated MAIT cell abundance. Collectively, our findings indicate that MAIT cells serve important but diverse roles in human cancers. Our work provides useful models and resources that employ gene expression data platforms to enable future studies in the realm of MAIT cell biology.

Highlights

  • The composition and the activity of immune cells within tumor microenvironments (TMEs) are important determinants of cancer progression or anticancer immunity and of clinical outcomes [1, 2]

  • While the degree of specificity for each mucosa-associated invariant T (MAIT) cell signature gene will likely vary between tissue compartments, disease states, individuals, and methods of measurement, these results suggest that the MAIT signature may be amenable to refinement in-context based on expected patterns of correlated gene expression

  • In the hepatocellular carcinoma (HCC) scRNA-seq dataset, we found that MAIT cells were reduced within tumors compared to the adjacent normal tissue and enriched in the healthy liver compared to peripheral blood, consistent with previous studies [19, 20, 42]

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Summary

Introduction

The composition and the activity of immune cells within tumor microenvironments (TMEs) are important determinants of cancer progression or anticancer immunity and of clinical outcomes [1, 2]. Several features of MAIT cells make them likely participants in either protective or pathogenic host responses to cancer and attractive targets in immunotherapeutic strategies First is their localization at common sites of oncogenesis, tumor growth and metastasis. Activated MAIT cells can produce a wide array of immunomodulatory cytokines, including IFN-γ, tumor necrosis factor (TNF)-α, and IL-17A, with varying secretion profiles depending on the tissue contexts and the means and modes of MAIT cell stimulation [30, 33, 34] Each of these cytokines can potentially influence cancer progression or antitumor defense mechanisms [46, 47]. MAIT cells were shown to destroy myeloma cell lines pulsed with MR1 ligands in vitro [22]

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