Insulin receptor substrate 2 phosphopeptide antigen (IRS2 phosphopeptide)

Insulin receptor substrate 2 (IRS2) phosphopeptide antigen is a post-translationally modified tumor-associated antigen (TAA) derived from the IRS2 protein, which serves as a cytoplasmic adapter for insulin and IGF-1 receptors (UniProt P35570). In various malignancies, such as melanoma and ovarian cancer, dysregulated kinase activity leads to the aberrant phosphorylation of IRS2, producing specific phosphopeptides that are processed and presented by MHC class I molecules, notably HLA-A*02:01 (Zarling et al., 2006, PNAS). These phosphopeptides represent a unique class of antigens that allow the immune system to detect the oncogenic signaling state of a cell (Cobbold et al., 2013, Science Translational Medicine). Therapeutic approaches targeting this antigen include TCR-engineered T-cells and phosphopeptide-based vaccines designed to elicit a robust cytotoxic T-lymphocyte response against tumor cells. Because these phosphorylation patterns are significantly more prevalent in cancerous tissues than in healthy ones, they offer a high degree of tumor specificity. However, potential safety concerns include off-target reactivity if similar phosphopeptides are presented at lower levels in vital organs like the liver or brain where IRS2 signaling is physiologically active.

Other names

pIRS2 antigenIRS2-derived phosphopeptidePhospho-IRS2 peptideMHC-presented IRS2 phosphopeptide

T-cell mediated cytotoxicity via T-cell receptor (TCR) recognition of MHC-presented phosphopeptides leading to tumor cell lysis.