# Investigation into the Endogenous Ligand Repertoire of the Non-Classical MHC-Related Protein, MR1 in Multiple Myeloma Cell Lines

> **NIH NIH R21** · UNIVERSITY OF CHICAGO · 2022 · $238,576

## Abstract

Project Abstract:
Major Histocompatibility Complex (MHC) molecules have been long been appreciated as the bridge between
the innate and adaptive immune cell populations. Beyond the peptide-presenting classical MHC class I and II
molecules, there exists a variety of other structurally related proteins in humans that have been found to present
diverse antigen types to a variety of T cell sub-types. Among these is the monomorphic MHC-related protein 1
(MR1) which is historically known for the presentation of microbially-derived riboflavin metabolites to Mucosal-
Associated Invariant T (MAIT) cells. Expanding on this initial observation, our group and others have shown that
the ligandome of MR1 is much more diverse than previously appreciated. MR1 is capable of presenting ligands
of various sizes and chemical structures beyond the originally described ribityl metabolites to a vast array of
MR1-restricted T cells (MR1Ts) carrying fully rearranged αβ TCRs. Recently, there have been emerging reports
of MR1T clones that have shown MR1-dependent cytotoxic activity against cancerous tissues in the complete
absence of any microbial infection or microbial ligands. Due to the unprecedented nature of these observations
and the potential impact of an MR1-based immunotherapy, it is important that the ligands being presented by
MR1 in the context of cancer-induced cellular disfunction be identified. Taking into consideration our own
research and these novel reports, we propose that MR1 acts as a sensor of the cellular metabolome in both the
context of microbial infection and endogenous disfunction like cancer, presenting a diverse array of metabolite
antigens. Due to our established track record investigating the biochemistry of MR1 and our existing collaborative
ligand discovery pipeline for MR1, The Adams Lab is uniquely poised to investigate the identity of the antigens
that MR1 is presenting in the context of cancer. Our investigation will focus on the plasma cell cancer, multiple
myeloma, as cell lines of this cancer have been shown to have abnormally high expression of MR1 at the cell
surface, indicating a higher possible antigenic load. We propose that our established microbial-ligand discovery
pipeline for MR1 can be adapted to investigate the tumor associated antigens (TAAs) being presented on the
surface of myeloma cells by either expressing our MR1 construct directly in these cell lines or by adding their
lysate into the media of transfected producing cells; both techniques that we have used before. Identification of
the ligands loaded into MR1 from these experiments will be determined by LC-MS/MS through our collaboration
with the Hildebrand Lab at the Oklahoma University Health Sciences Center. Following this determination, we
will capitalize on our structural biology expertise to determine how potential ligands bind the MR1 pocket. Finally,
we will use MR1/TAA tetramers to stain MR1T clones from donor blood samples and investigate their
transcriptio...

## Key facts

- **NIH application ID:** 10452305
- **Project number:** 1R21AI163554-01A1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Erin June Adams
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $238,576
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10452305

## Citation

> US National Institutes of Health, RePORTER application 10452305, Investigation into the Endogenous Ligand Repertoire of the Non-Classical MHC-Related Protein, MR1 in Multiple Myeloma Cell Lines (1R21AI163554-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10452305. Licensed CC0.

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