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

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24562-2

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DOI: 10.1038/s41467-021-24562-2

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