Ras-related C3 botulinum toxin substrate 1 (RAC1) P29S neoepitope peptide presented by HLA-A*02:01 (RAC1 P29S/HLA-A*02:01)

The RAC1 P29S neoepitope peptide presented by HLA-A*02:01 is a tumor-specific antigen resulting from a recurrent somatic mutation in the RAC1 gene, primarily found in cutaneous melanoma (Krauthammer et al., 2012, Nature Genetics). The P29S mutation (Proline to Serine at position 29) occurs in the switch I domain of the RAC1 GTPase, leading to constitutive protein activation and enhanced downstream signaling that drives tumor growth and metastasis (UniProt P63000). This mutation creates a novel peptide sequence, specifically the 9-mer FSGEYIPTV, which is processed and presented on the cell surface by the HLA-A*02:01 major histocompatibility complex (MHC) class I molecule (van Rooij et al., 2013, J Clin Oncol). Because this specific peptide-MHC complex is absent in healthy tissues, it serves as an ideal target for precision immunotherapies such as T-cell receptor (TCR) engineered T cells and personalized neoantigen vaccines. These therapies aim to harness the immune system to selectively recognize and eliminate RAC1 P29S-positive tumor cells while minimizing damage to normal cells. However, the clinical efficacy of targeting this neoepitope can be limited by tumor heterogeneity, HLA loss, or potential cross-reactivity with the wild-type RAC1 sequence if the TCR is not sufficiently specific. Ongoing research focuses on identifying high-affinity TCRs that can effectively target this complex in patients with the HLA-A*02:01 genotype.

Other names

RAC1 P29S neoantigenRAC1 P29S-HLA-A2 complexFSGEYIPTV-HLA-A*02:01RAC1 P29S (28-36) peptideMutant RAC1 P29S peptide-MHC complex

Recognition of the mutant peptide-HLA complex by engineered or vaccine-induced T-cell receptors (TCRs), leading to T-cell activation, cytokine release, and cytotoxic killing of the tumor cell.