Tumor neoantigen–peptide–Major Histocompatibility Complex (neoAg-pMHC)

Tumor neoantigen–peptide–Major Histocompatibility Complex (pMHC) complexes are molecular structures on the surface of cancer cells that present mutated protein fragments to the immune system (Schumacher & Schreiber, Science, 2015). These complexes are formed when somatic mutations in the tumor genome result in novel amino acid sequences (neoantigens) that are processed and loaded onto MHC Class I or II molecules (Blass & Ott, Nature Reviews Clinical Oncology, 2021). Because these neoantigens are entirely absent from the normal human proteome, the resulting pMHC complexes serve as highly specific "non-self" markers, allowing the immune system to distinguish malignant cells from healthy tissue with high precision (Yarchoan et al., Nature Reviews Cancer, 2017). Recognition of these complexes by T-cell receptors (TCRs) triggers a cytotoxic immune response aimed at destroying the malignant cell (Sahin & Türeci, Science, 2018). Therapeutic strategies targeting these complexes include personalized cancer vaccines, such as mRNA-4157, and adoptive cell therapies using TCR-engineered T cells (TCR-T) (Ott et al., Nature, 2017). However, the clinical utility of targeting pMHC complexes is often challenged by tumor evolution, which can lead to the downregulation of MHC expression or the loss of specific HLA alleles (Gettinger et al., Cancer Discovery, 2017). Additionally, the high degree of patient specificity for most neoantigens necessitates a personalized approach to drug development, posing significant logistical and manufacturing hurdles.

Other names

Neoantigen-MHC complexpMHC complexNeoepitope-HLA complexTumor-specific antigen-MHC complexpHLA complex

Recognition by T-cell receptors (TCRs) or TCR-like agents to trigger targeted lysis of tumor cells by cytotoxic T lymphocytes.