Tumor-associated antigen-Major Histocompatibility Complex (TAA-MHC)

Tumor-associated antigen-Major Histocompatibility Complex (TAA-MHC) refers to the presentation of intracellular or membrane-derived tumor peptides on the cell surface by MHC molecules for recognition by T-cell receptors (TCRs). This target class is fundamental to cellular immunity, as it allows the immune system to detect internal cellular abnormalities, such as oncogenic transformations, that are not accessible to traditional antibodies [Nature Reviews Cancer, 2021]. Therapeutic interventions targeting TAA-MHC complexes include TCR-engineered T-cell (TCR-T) therapies and TCR-bispecific engagers, which are engineered to bind specific peptide-HLA combinations with high affinity [Frontiers in Immunology, 2020]. These therapies are highly specific to both the peptide sequence and the patient's HLA allele, most commonly HLA-A*02:01, necessitating precise patient screening [Journal of Hematology & Oncology, 2023]. Upon successful binding, the therapeutic agent triggers T-cell activation, leading to the release of cytotoxic molecules like granzymes and perforins that induce apoptosis in the tumor cell [Science, 2019]. Key examples of this target class include MAGE-A4 and gp100 peptides presented on HLA-A*02:01, which have led to the approval of therapies like afamitresgene autoleucel and tebentafusp [FDA, 2022/2024]. This approach expands the druggable proteome by targeting the approximately 90% of proteins that are intracellular [Molecular Cancer, 2022]. However, challenges remain, including the risk of off-target cross-reactivity with similar peptides in healthy tissues and the potential for tumor escape through HLA downregulation [Nature Communications, 2023].

Other names

Peptide-MHC complexpMHCTumor-specific antigen-MHCNeoantigen-MHC complexCancer-testis antigen-MHCTAA-HLA complex

T-cell receptor (TCR) mediated recognition of specific peptide-MHC complexes on the tumor cell surface, triggering T-cell activation, cytokine release, and directed lysis of the target cell via perforin and granzymes [Science, 2019].