Mutant RAS peptide–HLA class I complex (RAS-HLA-I)

Mutant RAS peptide–HLA class I complexes are neoantigens formed when mutated RAS proteins (such as KRAS, NRAS, or HRAS) are processed by the proteasome and the resulting mutant peptides are presented on the cell surface by Human Leukocyte Antigen (HLA) class I molecules (Tran et al., 2016, NEJM). These complexes are highly specific to tumor cells because the mutant peptides are not found in normal tissues, making them ideal targets for precision immunotherapy (Sim et al., 2020, Cancer Cell). They are primarily recognized by the T-cell receptors (TCRs) of CD8+ T cells, which can trigger a potent cytotoxic immune response against the cancer cell (Bear et al., 2020, Nature Communications). Therapeutic strategies targeting these complexes include TCR-engineered T-cell (TCR-T) therapies and bispecific T-cell engagers, which are currently in clinical development for RAS-driven malignancies (NCT03190941; NCT04520711). These approaches are particularly relevant for cancers with high RAS mutation frequencies, such as pancreatic ductal adenocarcinoma, colorectal cancer, and non-small cell lung cancer (Prior et al., 2020, Cancer Research). A significant challenge in targeting these complexes is the high degree of HLA polymorphism, requiring therapies to be matched to a patient's specific HLA genotype, such as HLA-A*11:01 or HLA-C*08:02 (Wang et al., 2021, Frontiers in Immunology). Additionally, tumors may develop resistance by downregulating HLA expression or through other mechanisms of immune evasion (Garrido et al., 2016, Cancer Immunology, Immunotherapy).

Other names

Mutant RAS-MHC class I complexKRAS neoantigen-HLA complexRAS-derived neoantigen-HLA complexMutant RAS peptide-MHC-IKRAS G12D-HLA-A*11:01 complex

T-cell receptor (TCR) mediated recognition of the mutant peptide-HLA complex, leading to T-cell activation, secretion of cytotoxic granules (perforin and granzymes), and induction of apoptosis in the target tumor cell (Tran et al., 2016, NEJM).