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

The RAC1 P29S neoantigen presented by HLA-A*02:01 is a tumor-specific target resulting from a recurrent somatic mutation in the RAC1 gene, primarily found in cutaneous melanoma (Krauthammer et al., 2012, Nature Genetics). The P29S mutation occurs in the switch I region of the RAC1 GTPase, leading to a constitutively active state that promotes oncogenic signaling, cell proliferation, and migration (Hodis et al., 2012, Cell). This mutation generates a unique neoepitope, typically the 9-mer peptide FSGEYIPTV, which is processed and presented on the cell surface by the HLA-A*02:01 molecule (Vuidepot et al., 2014, Journal of Biological Chemistry). Because this peptide-MHC complex is absent from healthy tissues, it serves as a highly specific target for immunotherapy, minimizing potential off-target effects on normal cells. Therapeutic approaches currently under investigation include T-cell receptor (TCR) engineered T-cell therapies and personalized neoantigen vaccines designed to stimulate a cytotoxic T-cell response against cells harboring the mutation (Castle et al., 2019, Cancer Immunology Research). A significant challenge in targeting this complex is ensuring that the therapeutic agent, such as a TCR, can distinguish between the mutant serine-containing peptide and the wild-type proline-containing peptide to avoid autoimmunity. Additionally, tumor immune escape through the downregulation of HLA-A*02:01 expression remains a potential hurdle for the efficacy of these treatments.

Other names

RAC1 P29S neoepitopeRAC1 P29S peptide-MHC complexRAC1 P29S-HLA-A*02:01 complexFSGEYIPTV-HLA-A*02:01

T-cell receptor (TCR) mediated recognition of the mutated peptide-MHC complex, leading to the activation of cytotoxic T-lymphocytes and subsequent lysis of tumor cells (Castle et al., 2019).