MR1-Restricted T Cells Are Unprecedented Cancer Fighters

Abstract

Non-polymorphic MHC class I-related molecule MR1 presents antigenic bacterial metabolites to mucosal-associated invariant T (MAIT) cells and self-antigens to MR1-restricted T (MR1T) cells. Both MR1-restricted T cell populations are readily identified in healthy individuals, with MAIT cells accounting for 1-10% of circulating T cells, while MR1T cells have frequencies comparable to peptide-specific T cells (<0.1%). Self-reactive MR1T cells display a heterogeneous phenotype, and are capable of releasing both T H1 and T H2 cytokines, supporting not only activation of inflammation but also contributing to its regulation. Importantly, MR1T cells recognize and kill a diverse range of MR1-expressing tumor cells. On the other hand, evidence suggests MAIT cells augment cancer growth and metastases. This review addresses the potential role of MR1-restricted T cells in controlling tumor cells, facilitating their elimination and regulating cancer immunity. We also discuss therapeutic opportunities surrounding MR1-restricted T cells in cancer.

Airway Natural Killer Cells and Bacteria in Health and Disease

“…For tissue-based studies, the differences might be more blunted, although ILC1 are considered as non-cytotoxic cells ( 110 – 112 ). These difficulties are in line with the increasing number of “new” cell types that are currently discovered [for example MR1 T cells ( 113 )], as a consequence of the ever growing diversification and performance of the experimental tools in immunology.…”

MR1-Restricted T Cells in Cancer Immunotherapy

“…MAIT cells are activated by MR1 in complex with metabolites produced by bacteria and fungi of the human microbiome, especially the gut microbiota [ 27 , 28 , 29 , 30 ]. In addition, they are capable of mounting an immune response against tumor antigens [ 12 , 13 , 24 , 28 , 30 ]. It appears that the renewal of the MAIT cell compartment is maintained by constant stimulation of MAIT cells or their precursors in the mucosa.…”

“…It is interesting that MAIT cells or different subsets of MAIT cells appear to play dichotomous roles, promoting the growth of or eliminating cancer cells [ 12 , 13 , 28 ]. One school of thought is that MAIT cells may promote cancer growth at early stages of tumorigenesis and eliminate cancer cells at late stages [ 12 , 13 , 28 ]. We reasoned that this dual role might have to do with the subtype of MAIT cells infiltrating the tumor and/or the tumor microenvironment.…”

“…On the other hand, IL-17 family members may elicit immune defense against tumors by orchestrating anti-tumor activity by promoting the secretion of chemokines that attract tumor-suppressive lymphocytes, such as CD8 + T cells, to the tumor [ 45 , 46 ]. In addition to IL-17 production for host defense against tumors, MAIT cells are able to directly eliminate tumor cells through the expression of perforin and granzyme B after activation through their TCRs, which are specific against target tumor cells expressing MR1 in complex with metabolite antigens in the plasma membrane [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 28 , 30 , 31 , 41 , 47 ]. Moreover, IL-17A is known to stimulate tumor cell proliferation and metastasis in non-small-cell lung cancer and breast cancer [ 48 , 49 , 50 , 51 , 52 ].…”

“…The major histocompatibility complex (MHC) class I-related (MR1) is a cell membrane protein expressed in cells infected by certain types of bacteria or in cells under metabolic stress [ 7 , 8 , 9 , 10 , 11 ]. Tumor cells also express MR1 [ 12 , 13 ]. Unlike the highly polymorphic MHC-I molecules, MR1 is monomorphic.…”