Human leukocyte antigen-presented tumor antigens (pHLA)

Human leukocyte antigen (HLA)-presented tumor antigens are short peptide fragments derived from intracellular or membrane proteins that are processed and displayed on the cell surface by HLA molecules (Nature Reviews Cancer, 2021). These complexes are the primary targets for T-cell-mediated immunity, as T-cell receptors (TCRs) specifically recognize the combination of the peptide and the HLA groove. In cancer, these antigens include neoantigens derived from somatic mutations, cancer-testis antigens like MAGE-A4, and overexpressed self-antigens like gp100 (Lancet, 2024). Therapeutic interventions such as TCR-engineered T-cell therapies (e.g., Afamitresgene autoleucel) and bispecific T-cell engagers (e.g., Tebentafusp) aim to exploit these targets to direct the immune system against malignant cells (NEJM, 2022). Because HLA molecules present peptides from the entire cellular proteome, they provide access to a much broader range of targets than conventional antibody-based therapies, which are limited to surface-expressed proteins. However, the effectiveness of these therapies is often limited by the high diversity of HLA alleles across the population and the ability of tumors to downregulate HLA expression to evade immune detection.

Other names

Tumor-associated antigensTumor-specific antigensNeoantigensPeptide-MHC complexesCancer-testis antigenspHLAMHC-presented peptidesTumor neoepitopes

Recognition of specific peptide-HLA complexes by T-cell receptors (TCRs) or TCR-mimetic antibodies to induce T-cell mediated lysis of tumor cells (Nature Reviews Drug Discovery, 2021).