Tumor-derived peptide–Major Histocompatibility Complex class I (pMHC-I)

Tumor-derived peptide–Major Histocompatibility Complex class I (pMHC-I) complexes are molecular assemblies on the surface of tumor cells that present intracellularly processed protein fragments to the immune system [1]. These complexes consist of a polymorphic MHC class I heavy chain (HLA-A, -B, or -C in humans), a light chain (beta-2 microglobulin), and a short peptide ligand derived from mutated (neoantigens) or overexpressed (tumor-associated antigens) proteins [2]. They function as the primary recognition unit for CD8+ T-cell receptors (TCRs), enabling the immune system to identify and eliminate malignant cells [1, 4]. In drug development, pMHC-I complexes are targeted by innovative modalities such as TCR-engineered T cells (TCR-T), bispecific T-cell engagers (ImmTACs), and TCR-mimic antibodies, which allow for the targeting of intracellular oncogenic drivers [2, 3]. Despite their high specificity, therapeutic challenges include the potential for lethal cross-reactivity with similar peptides in healthy tissues and the loss of MHC expression by tumors as a mechanism of acquired resistance [1, 2]. References: [1] https://pmc.ncbi.nlm.nih.gov/articles/PMC10532533/ [2] https://www.nature.com/articles/s41573-021-00232-4 [3] https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-afamitresgene-autoleucel-synovial-sarcoma [4] https://pubmed.ncbi.nlm.nih.gov/34163011/

Other names

Peptide-MHC class I complexpMHC-I complexHLA-peptide complexTumor antigen-MHC complexNeoantigen-MHC complexTumor-associated antigen-MHC complex

Recognition by engineered T-cell receptors (TCRs) or TCR-mimic antibodies to induce T-cell activation, cytokine secretion, and cytotoxic lysis of tumor cells [1, 2].