Nucleobase adduct-containing metabolites are MR1 ligands that stimulate self-reactive MR1T cells

Abstract

MR1T lymphocytes are a recently identified population of T cells that recognize unknown self-antigens presented by the non-polymorphic MHC-I-related molecule, MR1. MR1T cells can kill tumor cells and modulate the functions of other immune cells with promising therapeutic applications. By integrating genetic, pharmacological and biochemical approaches we identified carbonyl stress and alterations of nucleobase metabolism in tumor target cells that promote recognition by MR1 T cells. We dissected these pathways and found that nucleobase adduct-containing metabolites are self-antigens stimulating MR1T cells. Several nucleobase adducts are presented by MR1 molecules and stimulate individual MR1T cells. Our data suggest that MR1T cells are surveyor of cellular metabolic alterations occurring in conditions of metabolic stress, such as cancer, and lay the groundwork for the development of novel HLA-unrestricted T cell-based therapies.

Targeting pediatric cancers via T-cell recognition of the monomorphic MHC class I-related protein MR1

“…We next compared single cell sequencing data of the two screened HBL models that were established from the same patient, of which HB13F was susceptible to MC.7.G5 MR1T-cell targeting, while HB13E was resistant. While we observe major differences in both immunogenicity ( figure 2F ) and metabolic pathway enrichment ( figure 2G ) between the two models, we do not find enrichment of metabolic gene sets involved in nucleobase adduct generation and formation of reactive oxygen species, two processes recently suggested to be important in generation of MR1 presentable antigens 8 ( online supplemental figure S6 ).…”

“…Overexpression of MR1 in resistant cell lines, however, did sensitize cells to MC.7.G5 cytotoxicity, indicating that the targeted antigen is present in these resistant models. Unraveling the presented metabolite(s) 8 to MR1T is key to efficiently predict, and potentially pharmacologically increase, sensitivity to MR1T-cell cytotoxicity.…”

“…Interestingly, a more recent CRISPR-Cas9 screen using several other MR1T-cell clones, found that formation of nucleobase adducts, reactive oxygen species, and carbonyl species are all important in the formation of the MR1presented antigenic metabolite(s). 8 on June 3, 2024 by guest. Protected by copyright.…”

“… 3 6 These MR1T-cells recognize MR1-presented cancer-specific metabolite(s) on the cell surface of cancer cells, the exact nature of which remains unidentified. 8 Crowther and colleagues isolated an MR1-restricted, tumor-reactive T-cell clone from peripheral blood of a healthy donor. 6 The clone is irresponsive to healthy tissue, while conferring HLA-independent cytotoxicity towards a diverse array of adult cancer cells.…”