MHC-related protein 1–restricted recognition of cancer via a semi-invariant TCR-α chain
Garry Dolton, … , Barbara Szomolay, Andrew K. Sewell
Garry Dolton, … , Barbara Szomolay, Andrew K. Sewell
Published January 2, 2025
Citation Information: J Clin Invest. 2025;135(1):e181895. https://doi.org/10.1172/JCI181895.
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Research Article Immunology Oncology

MHC-related protein 1–restricted recognition of cancer via a semi-invariant TCR-α chain

Abstract

The T cell antigen presentation platform MR1 consists of 6 allomorphs in humans that differ by no more than 5 amino acids. The principal function of this highly conserved molecule involves presenting microbial metabolites to the abundant mucosal-associated invariant T (MAIT) cell subset. Recent developments suggest that the role of MR1 extends to presenting antigens from cancer cells, a function dependent on the K43 residue in the MR1 antigen binding cleft. Here, we successfully cultured cancer-activated, MR1-restricted T cells from multiple donors and confirmed that they recognized a wide range of cancer types expressing the most common MR1*01 and/or MR1*02 allomorphs (over 95% of the population), while remaining inert to healthy cells including healthy B cells and monocytes. Curiously, in all but one donor these T cells were found to incorporate a conserved TCR-α chain motif, CAXYGGSQGNLIF (where X represents 3–5 amino acids), because of pairing between 10 different TRAV genes and the TRAJ42 gene segment. This semi-invariance in the TCR-α chain is reminiscent of MAIT cells and suggests recognition of a conserved antigen bound to K43.

Authors

Garry Dolton, Hannah Thomas, Li Rong Tan, Cristina Rius Rafael, Stephanie Doetsch, Giulia-Andreea Ionescu, Lucia F. Cardo, Michael D. Crowther, Enas Behiry, Théo Morin, Marine E. Caillaud, Devinder Srai, Lucia Parolini, Md Samiul Hasan, Anna Fuller, Katie Topley, Aaron Wall, Jade R. Hopkins, Nader Omidvar, Caroline Alvares, Joanna Zabkiewicz, John Frater, Barbara Szomolay, Andrew K. Sewell

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Figure 6

MR1-restricted TCRs do not react to healthy cells and are cancer specific.

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MR1-restricted TCRs do not react to healthy cells and are cancer specifi...
(A) CD69 assay (24 hours) of MC.27.759S and MC.7.G5 TCR-transduced Jurkat cells with cancer cell lines MEL526 (melanoma, MR1*01/*02) and MCF-7 (breast, MR1*01/*02), and purified (CD14+) monocytes (M). MR1T TCR JMA in Jurkat cells used as a positive control for monocyte recognition. Duplicate conditions. (B) CD69 assay (24 hours) of MC.27.759S and MC.7.G5 TCR-transduced Jurkat cells with cancer cell lines ACHN (kidney, MR1*01) and FM74 (melanoma, MR1*01), and purified (CD19+) B cells. CD19-chimeric antigen receptor (CAR) expressed in Jurkat cells were used as a positive control for B cell recognition. Duplicate conditions. (C) CD69 assay (24 hours) of K8T-1 and K8T-2 TCR-transduced Jurkat cells cancer cell line K-562 (leukemia/CML, MR1*01), and purified monocytes (CD14+) and B cells (CD19+). JMA TCR and CD19-CAR in Jurkat cells were used as positive controls for healthy cell recognition. Duplicate conditions. (D) Repeated CD69 assay (24 hours, conditions in triplicate with error bars depicting SD) using the above TCRs and CD19-CAR with monocytes (M) and B cells (B) from 3 healthy donors and cancer cell line FM72 (melanoma, MR1*01).