Characterization of Tumor-Infiltrating Lymphocyte-Derived Atypical TCRs Recognizing Breast Cancer in an MR1-Dependent Manner

The MHC class I-related 1 (MR1) molecule is a non-polymorphic antigen-presenting molecule that presents several metabolites to MR1-restricted T cells, including mucosal-associated invariant T (MAIT) cells. MR1 ligands bind to MR1 molecules by forming a Schiff base with the K43 residue of MR1, which induces the folding of MR1 and its reach to the cell surface. An antagonistic MR1 ligand, Ac-6-FP, and the K43A mutation of MR1 are known to inhibit the responses of MR1-restricted T cells. In this study, we analyzed MR1-restricted TCRs obtained from tumor-infiltrating lymphocytes (TILs) from breast cancer patients. They responded to two breast cancer cell lines independently from microbial infection and did not respond to other cancer cell lines or normal breast cells. Interestingly, the reactivity of these TCRs was not inhibited by Ac-6-FP, while it was attenuated by the K43A mutation of MR1. Our findings suggest the existence of a novel class of MR1-restricted TCRs whose antigen is expressed in some breast cancer cells and binds to MR1 depending on the K43 residue of MR1 but without being influenced by Ac-6-FP. This work provides new insight into the physiological roles of MR1 and MR1-restricted T cells.