Tumor-associated and tumor-specific antigens presented on MHC to TCR (TAA/TSA-MHC complex)

Tumor-associated and tumor-specific antigens presented on MHC to TCR represent a critical class of therapeutic targets in oncology, forming the basis for cellular therapies and cancer vaccines (Schuster et al., 2018, Nature Reviews Drug Discovery). These targets consist of short peptide fragments derived from intracellular proteins—either overexpressed (TAAs) or mutated (TSAs/neoantigens)—that are processed and displayed on the cell surface by Major Histocompatibility Complex (MHC) molecules. Recognition of these peptide-MHC complexes by T-cell receptors (TCRs) is the primary mechanism by which the adaptive immune system identifies and eliminates malignant cells. Therapeutic strategies include TCR-engineered T-cells (TCR-T), bispecific TCR-directed therapies, and peptide vaccines designed to prime the immune system against these specific signatures. Because these targets allow access to the intracellular proteome, they expand the range of druggable cancer targets beyond surface proteins. However, challenges include the requirement for specific HLA types in patients and the risk of lethal cross-reactivity if the target peptide resembles those found in vital organs. Successful targeting requires high specificity to avoid damaging healthy tissues that may express low levels of the antigen or similar peptide sequences.

Other names

Tumor antigensNeoantigensCancer-testis antigensPeptide-MHC complexpMHCHLA-restricted antigensTumor-specific antigens (TSA)Tumor-associated antigens (TAA)

Drugs targeting these complexes typically function by providing a synthetic or engineered T-cell receptor (TCR) or TCR-mimetic antibody that recognizes the specific peptide-MHC combination, leading to T-cell mediated lysis of the tumor cell (Nathan et al., 2022, NEJM).