Tumor cells expressing patient-specific peptide–MHC and stress ligands

Tumor cells expressing patient-specific peptide–MHC (pMHC) and stress ligands represent a composite target for advanced cancer immunotherapies. The pMHC component involves neoantigens—mutated peptides unique to the patient's tumor—presented by Major Histocompatibility Complex molecules, which serve as specific signatures for T-cell receptor (TCR) recognition (Schumacher & Schreiber, Science, 2015). Stress ligands, including MICA, MICB, and ULBP proteins, are upregulated on malignant cells due to genomic instability and serve as danger signals for the NKG2D receptor on Natural Killer (NK) and T-cells (Lanier, Cancer Immunol Res, 2015). This target profile is utilized by adoptive cell therapies, such as TCR-engineered T-cells (TCR-T) and NKG2D-CAR T-cells, to direct a potent immune response against the tumor (June et al., NEJM, 2018). By targeting both the high specificity of neoantigens and the broad stress signals of cancer, these therapies aim to minimize off-target effects while overcoming tumor heterogeneity. However, challenges include the potential for tumor escape through MHC downregulation or the shedding of soluble stress ligands (Dhar & Wu, Front Immunol, 2018).

Other names

Neoantigen-MHC and stress ligand-expressing tumor cellspMHC and NKG2D ligand complexTumor-specific antigen-MHC and stress-induced ligands

Therapeutic agents target this complex by employing engineered T-cell receptors (TCRs) or chimeric antigen receptors (CARs) that bind to the specific peptide-MHC or stress ligands, triggering the release of cytotoxic granules and pro-inflammatory cytokines to induce tumor cell lysis.