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Systematic Discovery and Validation of T Cell Targets Directed Against Oncogenic KRAS Mutations

ABSTRACT: Jaewon Choi, Scott P. Goulding, Brandon P. Conn, Christopher D. McGann, Jared L. Dietze, Jessica Kohler, Divya Lenkala, Antoine Boudot, Daniel A. Rothenberg, Paul J. Turcott, John R. Srouji, Kendra C. Foley, Michael S. Rooney, Marit M. van Buuren, Richard B. Gaynor, Jennifer G. Abelin, Terri A. Addona, and Vikram R. Juneja Oncogenic mutations in KRAS can be recognized by T cells on specific class I human leukocyte antigen (HLA-I) molecules, leading to tumor control. To date, the discovery of T cell targets from KRAS mutations has relied on occasional T cell responses in patient samples or the use of transgenic mice. To overcome these limitations, we developed a systematic target discovery and validation pipeline. We evaluated the presentation of mutant KRAS peptides on individual HLA-I molecules using targeted mass spectrometry (MS) and identified 13 unpublished KRASG12C/D/R/V mutation/HLA-I pairs and nine previously described pairs. We assessed immunogenicity, generating T cell responses to nearly all targets. Using cytotoxicity assays, we demonstrated that KRAS-specific T cells and T cell receptors (TCRs) specifically recognize endogenous KRAS mutations. The discovery and validation of T cell targets from KRAS mutations demonstrate the potential for this pipeline to aid the development of immunotherapies for important cancer targets.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Vikram R. Juneja

PROVIDER: MSV000087987 | MassIVE | Fri Aug 13 21:42:00 BST 2021

REPOSITORIES: MassIVE

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