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

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 TCR alpha beta 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. KRAS is commonly mutated at codon 12 in several cancer types, offering a unique opportunity for the development of neoantigen-targeted immunotherapy. Here the authors present a pipeline for the prediction, identification and validation of HLA class-I restricted mutant KRAS G12 peptides, leading to the generation of mutant KRAS-specific T cell receptors for adoptive T cell immunotherapy.

Automated summary

Activating RAS missense mutations are common in human cancers and can be immunologically targeted. By characterizing HLA class I-restricted mKRAS epitopes, the study successfully isolated and transferred mKRAS-specific TCR to CD8(+) T cells, demonstrating cytotoxicity against mKRAS tumor cells from various origins, with lytic activity correlating with peptide-HLA class I complex abundance. Adoptive transfer of mKRAS-TCR engineered CD8(+) T cells led to tumor eradication in a xenograft model, validating mKRAS peptides as epitopes for immune therapies.