T-cell receptor recognizing neoantigen peptide–HLA complex (NeoTCR-pHLA)

The T-cell receptor (TCR) recognizing a neoantigen peptide–HLA complex is a fundamental unit of tumor immunosurveillance and a high-priority target for personalized cancer immunotherapy [1.1.1, 1.4.2]. Neoantigens are unique peptides resulting from somatic mutations in tumor DNA, such as missense mutations or frameshifts, which are absent in the normal proteome [1.1.1, 1.4.2]. These peptides are processed and presented on the cell surface by Human Leukocyte Antigen (HLA) molecules, creating a highly specific non-self signal [1.1.2, 1.4.4]. T cells recognize these complexes through their heterodimeric TCRs, initiating a signaling cascade via the CD3 complex that leads to the release of cytotoxic granules and tumor cell lysis [1.1.3, 1.4.5]. Therapeutic interventions, such as TCR-engineered T-cell (TCR-T) therapy and TCR-mimic bispecific antibodies, aim to harness or enhance this recognition to treat advanced solid tumors and hematological malignancies [1.2.1, 1.2.3]. Unlike CAR-T cells, which recognize surface proteins, TCR-based therapies can target intracellular proteins that are processed and presented as peptides [1.1.2, 1.2.5]. Clinical development focuses on both public neoantigens shared across patients, such as KRAS or TP53 mutations, and highly personalized private neoantigens [1.4.2, 1.4.3]. Key challenges include the risk of off-target toxicity due to cross-reactivity with similar self-peptides and the potential for tumor resistance via HLA downregulation [1.3.1, 1.3.3]. Successful targeting requires precise matching of the TCR to both the specific neoantigen and the patient's HLA genotype [1.4.1, 1.4.3].

Other names

Neoantigen-specific T-cell receptorNeoantigen-HLA complexNeoepitope-MHC complexTumor-specific TCR-pHLA interactionNeoTCR-pHLA complex

Adoptive T-cell therapy (TCR-T) involving the engineering of autologous or allogeneic T cells to express a specific TCR that binds the neoantigen-HLA complex, leading to T-cell activation and tumor cell lysis [1.2.4, 1.4.5].