Approximately 19% of cancer diagnoses are associated with a RAS mutation, and in roughly 75% of these cases, a mutation in KRAS has been detected. Choi et al. generated a panel of nine stably transduced cell lines. Each line expressed all four of the most common KRAS codon 12 mutations along with one HLA-1 allele. The peptides, which were bound to each HLA-I allele, were purified, sequenced, and tested for the ability to stimulate primary in vitro T cell responses. This work has doubled the number of known immunogenic KRAS-related neoantigens and provided a road map for systemic discovery of neoantigens in many different types of tumors.
Contributed by Margot O’Toole
ABSTRACT: 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 have developed a systematic target discovery and validation pipeline. We evaluate the presentation of mutant KRAS peptides on individual HLA-I molecules using targeted mass spectrometry and identify 13 unpublished KRASG12C/D/R/V mutation/HLA-I pairs and nine previously described pairs. We assess immunogenicity, generating T cell responses to nearly all targets. Using cytotoxicity assays, we demonstrate that KRAS-specific T cells and T cell receptors 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.
Author Info: (1) BioNTech US Inc., 40 Erie Street, Suite 110, Cambridge, MA 02139, USA. (2) These authors contributed equally. (3) senior author. (4) lead author.
Author Info: (1) BioNTech US Inc., 40 Erie Street, Suite 110, Cambridge, MA 02139, USA. (2) These authors contributed equally. (3) senior author. (4) lead author.
