MAIT cells regulate NK cell mediated tumor immunity

Abstract

MR1-restricted mucosal-associated invariant T (MAIT) cells recognize microbial metabolites and play an important role in immunity to infection, however, the role they play in tumor immunity is unclear. Here we show that MAIT cell-deficient mice are more resistant to subcutaneous and lung metastasis B16F10 tumor growth compared to control mice, an effect that was associated with enhanced NK cell numbers and was NK cell-dependent. Analysis of this interplay in cancer patients also revealed that a high expression of a novel MAIT gene signature negatively impacted the prognostic significance of NK cells. Paradoxically, pre-pulsing tumors with MAIT cell antigens, or antigen-mediated MAIT cell activation in vivo, enhanced immunity against B16F10 and E0771 lung tumor metastasis. Furthermore, MAIT cell activation effectively reduced metastatic burden in a more stringent model of established lung metastases in mice. These effects were associated with enhanced NK cell responses and increased expression of both IFNγ-dependent and inflammatory genes in NK cells, which was neutralized by IFNγ blockade. Importantly, activated human MAIT cells also enhanced the function of NK cells isolated from patient tumor samples. These findings provide insight into the contrasting roles that MAIT cells can play in controlling anti-tumor immune responses depending on their activation status, in both mice and humans, and suggest potential therapeutic avenues for exploiting their potential anti-tumor properties for cancer treatment.

Double‐negative T cells: Setting the stage for disease control or progression

“…Although early studies differ on the ontogeny of these cells, recent studies by Brozova et al have shown that CD8+ and DN MAIT subsets are related to memory/ effector, tissue-homing and pro-inflammatory activities, with DN MAIT cells expressing less cytotoxic activity and displaying a lower expression of granzyme and CD107a, when compared to CD8 + MAIT cells [40]. Many studies have shown that MAIT cells may play a role in protective immunity in the lung [41,42], oral mucosa [43] and several types of cancers and infectious diseases [44][45][46], although they are also implicated in various autoimmune disorders [47][48][49].…”

Mucosal‐associated invariant T cells: A cryptic coordinator in HIV‐infected immune reconstitution

“…25 MAIT cells also regulate the polarization of macrophages and promote the function of natural killer (NK) cells. 26,27 All these findings indicate the potential of MAIT cells in immune regulation. Despite no direct evidence of a role for MAIT cells in immune reconstitution in HIVinfected individuals, there is a potential link between poor immune reconstitution and MAIT cell disorders.…”

“…Additionally, microbial or cytokine‐stimulated MAIT cell supernatants contain a variety of cytokines that stimulate B cells, including IL‐6, IL‐10, and IL‐21, and MAIT cells increase the frequencies of plasmablasts and promote the production of immunoglobulin A (IgA), IgG, and IgM in an MR1‐dependent manner 25 . MAIT cells also regulate the polarization of macrophages and promote the function of natural killer (NK) cells 26,27 . All these findings indicate the potential of MAIT cells in immune regulation.…”

Chemical Modulators of Mucosal Associated Invariant T Cells

“…57 One strategy toward inhibitors is to first develop potent stable 5-OP-RU analogues. Not only might these be potentially useful vaccine adjuvants 43 and cancer immunotherapeutics, 45 but they are potentially also tightbinding ligands that offer clues to more drug-like scaffolds, tagging 58 of 5-OP-RU for monitoring cellular uptake, and structure−activity relationships that lead to stable and effective modulators of MR1 and MAIT TCR proteins.…”

“…MAIT cells are attractive vaccine targets, and 5-OP-RU ( 3 ) can confer antibacterial protection against Legionella longbeachae and Francisella tularensis infections in mice. − 5-OP-RU used as a treatment during chronic Mycobacterium tuberculosis infection in mice increased MAIT cell expansion and reduced bacterial loads . 5-OP-RU also conferred protection in mouse models of B16F10 (melanoma) and E0771 (breast) metastasized lung cancer, suggesting the potential for 5-OP-RU in cancer immunotherapy. Collectively, these findings highlight the importance of this natural product as a tool for MAIT cell immunology and immunotherapeutics.…”