KRAS neoantigenic peptide-MHC class I complex (KRAS-pMHC)

KRAS neoantigenic peptides presented on MHC class I molecules are tumor-specific antigens arising from somatic mutations in the KRAS gene, a key driver in human oncogenesis [Simanshu et al., 2017]. In many cancers, particularly pancreatic, colorectal, and lung adenocarcinomas, specific KRAS mutations like G12D or G12V result in the production of mutant proteins that are intracellularly processed into short peptides [Simanshu et al., 2017; Leidner et al., 2022]. These mutant peptides are then loaded onto Major Histocompatibility Complex (MHC) class I molecules and displayed on the tumor cell surface for recognition by CD8+ T cells [Leidner et al., 2022; Tran et al., 2016]. Because these neoantigens are uniquely expressed by malignant cells and absent in healthy tissues, they serve as high-precision targets for immunotherapies such as TCR-engineered T-cell (TCR-T) therapies and cancer vaccines [Leidner et al., 2022; Pant et al., 2024]. Targeting the KRAS-pMHC complex aims to bypass the "undruggable" nature of the KRAS protein itself by utilizing the immune system's ability to detect intracellular mutations via surface presentation [Leidner et al., 2022]. However, the therapeutic application is highly dependent on the patient's specific HLA haplotype and the tumor's ability to maintain antigen presentation machinery [Tran et al., 2016]. Successful targeting can lead to potent, selective tumor lysis while minimizing damage to normal tissues expressing wild-type KRAS [Leidner et al., 2022; Pant et al., 2024].

Other names

KRAS mutant peptide-HLA complexKRAS neoepitope-MHC complexMutant KRAS-HLA complexKRAS G12D-HLA-A*11:01 complexKRAS G12D-HLA-C*08:02 complex

T-cell receptor (TCR) mediated recognition of the mutant peptide-MHC complex leading to cytotoxic T-lymphocyte activation and tumor cell lysis [Leidner et al., 2022; Tran et al., 2016].