T cell receptor recognizing phosphorylated breast cancer anti-estrogen resistance protein 3–major histocompatibility complex (TCR-pBCAR3-MHC)

The T cell receptor (TCR) recognizing the pBCAR3–MHC complex is a specialized immune recognition system that targets a phosphorylated neoantigen presented on the surface of cancer cells (Engelhard et al., 2020). BCAR3 (Breast cancer anti-estrogen resistance protein 3) is a scaffold protein involved in cell signaling and migration, which is frequently overexpressed and aberrantly phosphorylated in malignancies such as melanoma and breast cancer (NCT01846143). A specific nine-amino acid phosphopeptide derived from BCAR3 (pBCAR3 126-134, sequence IMDR[pT]PEKL) is processed and presented by the Major Histocompatibility Complex (MHC) class I molecule HLA-A*02:01 (Frontiers in Immunology, 2021). This phosphopeptide-MHC (pMHC) complex serves as a highly specific tumor-associated target because the phosphate group on the threonine residue (pT130) creates a unique structural and electrostatic motif that can be selectively recognized by the TCR, distinguishing it from the unphosphorylated self-peptide (JCI Insight, 2022). Therapeutic strategies targeting this complex focus on harnessing the specificity of the TCR to induce a potent anti-tumor immune response. These include the development of peptide-based vaccines, such as those evaluated in Phase I clinical trials (e.g., NCT01846143), which aim to prime and expand endogenous pBCAR3-specific CD8+ T cells. Additionally, engineered TCR-T cell therapies and TCR-mimic (TCRm) antibodies are being explored to provide high-affinity recognition of the pBCAR3–HLA-A*02:01 complex (ResearchGate, 2021). By specifically targeting post-translationally modified antigens that are enriched in the tumor microenvironment, these therapies aim to overcome the limitations of targeting non-mutated self-antigens and improve the precision of cancer immunotherapy.

Other names

pBCAR3-HLA-A*02:01 complexPhospho-BCAR3(126-134) MHC complexpBCAR3-MHCpBCAR3-HLA-A2

Activation of CD8+ cytotoxic T lymphocytes (CTLs) to recognize and kill tumor cells presenting the pBCAR3 phosphopeptide on HLA-A*02:01.