Patient-specific tumor-associated antigen presented as peptide-MHC complex (Neoantigen-pMHC)

Patient-specific tumor-associated antigens, commonly known as neoantigens, are unique peptides derived from non-synonymous somatic mutations occurring within a patient's tumor genome (Schumacher & Schreiber, Science 2015). These peptides are processed by the intracellular machinery and presented on the tumor cell surface in the context of Major Histocompatibility Complex (MHC) molecules, forming a peptide-MHC (pMHC) complex (NIH National Cancer Institute). Unlike shared tumor-associated antigens, neoantigens are absent from the normal proteome, which provides a high degree of therapeutic selectivity and reduces the risk of central tolerance or autoimmune toxicity (Blass & Ott, Nature Reviews Clinical Oncology 2021). The recognition of these pMHC complexes by the T-cell receptor (TCR) is the critical event that triggers a cytotoxic T-lymphocyte response against the tumor. Therapeutic strategies targeting these complexes include personalized mRNA or peptide vaccines, such as mRNA-4157/V940, and adoptive cell therapies using neoantigen-specific tumor-infiltrating lymphocytes (TILs) or TCR-engineered T-cells (Nature Reviews Cancer, 2021). This target is a cornerstone of precision immuno-oncology, as it allows for treatments tailored to the unique mutational profile of an individual's cancer.

Other names

NeoantigenTumor-specific antigenTSANeoepitope-MHC complexMutation-derived antigenpMHC complex

Therapeutic agents targeting these complexes work by inducing or enhancing the recognition of tumor-specific neoepitopes by the patient's T-cells. Personalized vaccines prime the immune system to generate neoantigen-specific CD8+ and CD4+ T-cells, while adoptive cell therapies provide T-cells with receptors (TCRs) specifically engineered to bind the pMHC complex, leading to the formation of an immunological synapse and subsequent perforin/granzyme-mediated lysis of the tumor cell (Schumacher & Schreiber, Science 2015).