Patient-specific neoantigen–HLA complex and T-cell receptor (Neoantigen-HLA/TCR)

Patient-specific neoantigen–HLA complexes and their corresponding T-cell receptors (TCRs) represent the cornerstone of highly personalized cancer immunotherapy. Neoantigens are novel peptides derived from somatic mutations—such as single nucleotide variants, insertions/deletions, or gene fusions—that are unique to a patient's tumor and absent from healthy tissues (Schumacher & Schreiber, Science, 2015). These mutated peptides are processed and presented on the tumor cell surface by Human Leukocyte Antigen (HLA) molecules. The recognition of these neoantigen-HLA complexes by specific TCRs on CD8+ or CD4+ T-cells triggers a potent and selective immune response (Sahin et al., Nature, 2017). Because neoantigens are not subject to central thymic tolerance, TCRs with high affinity can be identified or engineered to target them without the high risk of autoimmunity associated with shared self-antigens. Therapeutic strategies leveraging this target include personalized neoantigen vaccines and adoptive cell transfer of TCR-engineered T-cells (TCR-T) (Leidner et al., NEJM, 2022). However, challenges remain, including the heterogeneity of neoantigen expression within tumors and the potential for immune evasion through HLA downregulation or loss of the mutated allele.

Other names

Neoepitope-HLA complexTumor-specific antigen (TSA)Neoantigen-specific T-cell receptorPersonalized neoantigen-HLA targetTumor-specific neoantigen (TSNA)Neoepitope-MHC complex

The mechanism involves the specific recognition of a tumor-exclusive mutated peptide (neoantigen) presented by a patient's Human Leukocyte Antigen (HLA) molecule by a cognate T-cell receptor (TCR). This interaction forms an immunological synapse, leading to the activation of T-cells, secretion of cytotoxic granules such as perforin and granzymes, and targeted lysis of the tumor cell (Schumacher & Schreiber, Science, 2015; Sahin et al., Nature, 2017).