Mutant Ras peptide-HLA class I complex (Mutant Ras-pMHC) (Mutant Ras-pMHC)

Mutant Ras peptide-HLA class I complexes are neoantigens formed when mutated Ras proteins (KRAS, NRAS, or HRAS) are processed by the proteasome and presented on the cell surface by Human Leukocyte Antigen (HLA) molecules (PubMed: 27959608). These complexes are highly tumor-specific because the oncogenic mutations, such as KRAS G12D, G12V, or G12C, are absent in healthy tissues, providing a precise target for immunotherapy (Nature: 10.1038/s41586-021-03315-3). In many aggressive cancers, including pancreatic, colorectal, and non-small cell lung cancer, Ras mutations are primary drivers of malignancy, making these pMHC complexes critical for immune recognition (NEJM: 10.1056/NEJMoa1609277). Therapeutic strategies targeting these complexes include T-cell receptor (TCR) engineered T-cells, bispecific antibodies, and neoantigen vaccines (Science Immunology: 10.1126/sciimmunol.abd5515). Because these targets represent intracellular proteins presented as fragments, they allow the immune system to target undruggable oncogenic drivers that cannot be reached by traditional monoclonal antibodies. However, clinical success is often challenged by the low density of these complexes on the tumor surface and the high degree of HLA polymorphism in the human population (Frontiers in Immunology: 10.3389/fimmu.2020.01898).

Other names

Mutant Ras neoantigenRas-pMHC complexKRAS mutant peptide-HLA complexMutant Ras-HLA-I complexOncogenic Ras neoepitope

T-cell receptor (TCR) mediated recognition of the mutant peptide-HLA complex, leading to T-cell activation, formation of an immunological synapse, and cytotoxic killing of the tumor cell via perforin and granzyme release (PubMed: 33649112).