MR1-Restricted T Cells in Cancer Immunotherapy

Abstract

Major histocompatibility complex class I-related (MR1) was first identified as a cell membrane protein involved in the development and expansion of a unique set of T cells expressing an invariant T-cell receptor (TCR) α-chain. These cells were initially discovered in mucosal tissues, such as the intestinal mucosa, so they are called mucosal-associated invariant T (MAIT) cells. MR1 senses the presence of intermediate metabolites of riboflavin and folic acid synthesis that have been chemically modified by the side-products of glycolysis, glyoxal or methylglyoxal. These modified metabolites form complexes with MR1 and translocate from the endoplasmic reticulum to the plasma membrane where MAIT cells’ TCRs recognize them. Recent publications report that atypical MR1-restricted cytotoxic T cells, differing from MAIT cells in TCR usage, antigen, and transcription factor profile, recognize an as yet unknown cancer-specific metabolite presented by MR1 in cancer cells. This metabolite may represent another class of neoantigens, beyond the neo-peptides arising from altered tumor proteins. In an MR1-dependent manner, these MR1-restricted T cells, while sparing noncancerous cells, kill many cancer cell lines and attenuate cell-line-derived and patient-derived xenograft tumors. As MR1 is monomorphic and expressed in a wide range of cancer tissues, these findings raise the possibility of universal pan-cancer immunotherapies that are dependent on cancer metabolites.

Alternative splicing of apoptosis genes promotes human T cell survival

“…Similarly, splicing events in genes encoding caspase-9 (caspase-9), IL12RB, and MR1 displayed sensitivity to CD28 costimulation by 48 hr of T cell stimulation ( Figure 3D–F ). Loss of IL12RB expression following T cell activation biases differentiation toward the Th1 fate ( Kano et al, 2008 ), while major histocompatibility complex class I-related (MR1) is recognized by and activates a unique type of T cells with an invariant TCR alpha chain ( Flores-Villanueva et al, 2020 ). However, given the role of CD28 costimulation in promoting T cell viability, we were most intrigued by the influence of CD28 on the alternative splicing of caspase-9 ( Figure 3D ).…”

The P5-type ATPase ATP13A1 modulates major histocompatibility complex I-related protein 1 (MR1)-mediated antigen presentation

“…Their high numbers and poised phenotype allow them to rapidly carry out effector functions in response to their cognate microbial antigens and place them at the interface between the innate and the adaptive immune system ( 22 , 23 ). Furthermore, the MR1 antigen presentation pathway is an attractive target for both therapeutic and vaccination strategies as the monomorphic nature of the presenting molecule renders it independent of individual variations in human leukocyte antigen (HLA) expression ( 24 , 25 , 26 , 27 , 28 ). A better understanding of this nonclassical antigen presentation pathway is, thus, crucial for harnessing the protective potential of MAIT cells in such therapeutic approaches.…”

Alternative Splicing of Apoptosis Genes Promotes Human T Cell Survival

“…Similarly, splicing events in genes encoding caspase-9 (caspase-9), IL12RB, and MR1 displayed sensitivity to CD28 costimulation by 48hrs of T cell stimulation ( Figure 3D-F ). Loss of IL12RB expression following T cell activation biases differentiation toward the Th1 fate (Kano et al, 2008), while major histocompatibility complex class I-related (MR1) is recognized by and activates a unique type of T cells with an invariant TCR alpha chain (Flores-Villanueva et al, 2020). However, given the role of CD28 costimulation in promoting T cell viability, we were most intrigued by the influence of CD28 on the alternative splicing of caspase-9 ( Figure 3D ).…”