Biochemical and functional characterization of mutant KRAS epitopes validates this oncoprotein for immunological targeting

Adham S. Bear, Tatiana Blanchard, Joseph Cesare, Michael J. Ford, Lee P. Richman, Chong Xu, Miren L. Baroja, Sarah McCuaig, Christina Costeas, Khatuna Gabunia, John Scholler, Avery D. Posey, Mark H. O’Hara, Anze Smole, Daniel J. Powell, Benjamin A. Garcia, Robert H. Vonderheide, Gerald P. Linette, Beatriz M. Carreno

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Activating RAS missense mutations are among the most prevalent genomic alterations observed in human cancers and drive oncogenesis in the three most lethal tumor types. Emerging evidence suggests mutant KRAS (mKRAS) may be targeted immunologically, but mKRAS epitopes remain poorly defined. Here we employ a multi-omics approach to characterize HLA class I-restricted mKRAS epitopes. We provide proteomic evidence of mKRAS epitope processing and presentation by high prevalence HLA class I alleles. Select epitopes are immunogenic enabling mKRAS-specific TCRαβ isolation. TCR transfer to primary CD8+ T cells confers cytotoxicity against mKRAS tumor cell lines independent of histologic origin, and the kinetics of lytic activity correlates with mKRAS peptide-HLA class I complex abundance. Adoptive transfer of mKRAS-TCR engineered CD8+ T cells leads to tumor eradication in a xenograft model of metastatic lung cancer. This study validates mKRAS peptides as bona fide epitopes facilitating the development of immune therapies targeting this oncoprotein.

Original languageEnglish
Article number4365
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

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