Neoantigen peptide–Major Histocompatibility Complex class I (pMHC-I) (pMHC-I)

Neoantigen peptide–Major Histocompatibility Complex (MHC) class I complexes are the fundamental units of tumor recognition by the cellular immune system. They consist of a short peptide, typically 8-11 amino acids in length, derived from a tumor-specific somatic mutation that is processed and presented within the groove of an MHC class I molecule on the surface of malignant cells (NIH, 2022). Because these mutations are absent in healthy tissues, these complexes represent highly specific targets for immunotherapy, allowing the immune system to bypass central tolerance and minimize the risk of systemic autoimmunity (Frontiers in Immunology, 2024). In the context of oncology, the density and diversity of these complexes on the tumor surface are critical determinants of the efficacy of immune checkpoint inhibitors and the overall immunogenicity of the tumor (Lancet, 2024). Therapeutic strategies targeting these complexes include personalized mRNA or peptide vaccines, such as mRNA-4157 and BNT122, which are designed to prime endogenous T cells against a patient's unique mutational profile (Nature, 2023). Additionally, adoptive cell therapies (TCR-T) and bispecific T-cell engagers (ImmTACs) are being developed to provide high-affinity recognition of shared "hotspot" mutations, such as KRAS G12D, presented in the context of specific HLA alleles (Nature Communications, 2022). However, clinical success is often challenged by tumor-mediated immune escape mechanisms, such as the loss of HLA expression or the development of resistance to T-cell-mediated killing (NEJM, 2016).

Other names

Tumor-specific antigen (TSA) complexNeoepitope-MHC complexMutant peptide-MHC complexpHLA-I complexNeoantigen-HLA complex

Therapeutic agents targeting these complexes function by either priming the endogenous immune system to recognize them (vaccines) or by providing synthetic receptors (TCR-T, bispecifics) that bind the complex with high affinity. Recognition of the neoantigen-MHC complex by a T-cell receptor (TCR) triggers the formation of an immunological synapse, leading to the release of cytotoxic granules (perforin and granzymes) and the induction of apoptosis in the target tumor cell.