Phosphorylated Insulin Receptor Substrate 2 (1097-1105) peptide presented by HLA-A*02:01 (pIRS2(1097-1105)/HLA-A*02:01)

The pIRS2₁₀₉₇₋₁₁₀₅ phosphopeptide presented by HLA-A*02:01 is a tumor-associated phosphoneoantigen that serves as a specific target for cancer immunotherapy. This complex consists of a nine-amino acid fragment (RVApSPTSGV) from the Insulin Receptor Substrate 2 (IRS2) protein, which is phosphorylated at the serine-1100 residue and presented on the cell surface by the Human Leukocyte Antigen (HLA) allele A*02:01 (Zarling et al., 2006, Journal of Experimental Medicine). IRS2 is a critical adapter protein in the insulin and insulin-like growth factor 1 (IGF-1) signaling pathways, which are frequently dysregulated and overactive in various malignancies, including melanoma, breast cancer, and leukemia (Cobbold et al., 2013, Science Translational Medicine). Because the specific phosphorylation of this peptide is often a consequence of aberrant oncogenic kinase activity, the pMHC complex is preferentially displayed on cancer cells compared to healthy tissues. This high degree of tumor specificity makes it an attractive target for T-cell receptor (TCR)-based therapies, such as TCR-engineered T cells (TCR-T) and TCR-like antibodies (Mohammed et al., 2008, Journal of Immunology). These therapeutic approaches aim to exploit the immune system's ability to recognize post-translational modifications, providing a way to target the dark matter of the immunopeptidome that is not accessible by traditional antibody-based drugs. However, development challenges include ensuring high specificity to avoid cross-reactivity with the non-phosphorylated version of the peptide or other similar self-peptides.

Other names

pIRS2 phosphopeptide-MHC complexRVApSPTSGV/HLA-A*02:01Phospho-IRS2 (1097-1105) HLA-A2 complexpIRS2-1097 phosphopeptideIRS2 pS1100 phosphopeptide-HLA complex

Targeted immunotherapy via T-cell receptor recognition of tumor-specific phosphopeptide-MHC complexes