Tumor antigen–Major Histocompatibility Complex (pMHC)

Tumor antigen–Major Histocompatibility Complex (MHC) complexes, often referred to as peptide-MHC (pMHC) complexes, are the fundamental units of recognition for the adaptive immune system's T cells (Yee, 2023, Nature Reviews Clinical Oncology). These complexes consist of a short peptide fragment derived from intracellular proteins—which may be mutated, overexpressed, or lineage-specific in cancer—presented within the groove of an MHC molecule on the cell surface (He et al., 2022, Journal of Hematology & Oncology). In oncology, these complexes serve as highly specific markers that allow the immune system to distinguish malignant cells from healthy ones. Therapeutic strategies targeting these complexes include T-cell receptor (TCR) engineered T-cell therapies, TCR-bispecific engagers, and TCR-like antibodies, which bypass natural immune recognition to trigger T-cell mediated lysis (Akatsuka, 2017, Cancer Science). Because many tumor-specific antigens are intracellular and inaccessible to traditional antibodies, pMHC complexes represent a critical class of targets for accessing the intracellular proteome. Clinical success has been demonstrated with agents like Tebentafusp for uveal melanoma and Afamitresgene autoleucel for synovial sarcoma (Nathan et al., 2021, NEJM; D'Angelo et al., 2024, Lancet). However, challenges include the requirement for specific HLA-type matching in patients and the potential for tumor escape through MHC downregulation.

Other names

Peptide-MHC complexpMHCHLA-peptide complexTumor-specific antigen-MHC complexNeoantigen-MHC complexAntigen-presenting complex

Targeted recognition by engineered T-cell receptors (TCRs) or TCR-mimetic molecules to induce T-cell mediated cytotoxicity against cells presenting specific tumor-derived peptides.