Patient-specific tumor neoantigen–Human Leukocyte Antigen complex and T-cell receptor (NeoAg-HLA/TCR)

Patient-specific tumor neoantigen–Human Leukocyte Antigen (HLA) complexes are unique molecular targets formed when somatic mutations in a patient's tumor genome create novel protein sequences, known as neoantigens, which are processed and presented on the cell surface by HLA molecules [Source: Science, 2015]. These complexes are recognized by corresponding T-cell receptors (TCRs) on the surface of CD8+ and CD4+ T cells, serving as the primary signal for the immune system to distinguish malignant cells from healthy tissue. Because neoantigens are entirely absent from the normal human proteome, they are highly specific targets that minimize the risk of central tolerance and off-target autoimmunity [Source: Nature Reviews Genetics, 2021]. Therapeutic interventions targeting this interaction include personalized mRNA or peptide vaccines designed to prime the patient's immune system, as well as adoptive cell therapies like TCR-engineered T cells (TCR-T) or tumor-infiltrating lymphocytes (TILs) [Source: New England Journal of Medicine, 2020]. The efficacy of these therapies depends on the accurate identification of immunogenic neoepitopes and the presence of a functional antigen-presentation machinery within the tumor microenvironment. Despite their high specificity, challenges such as tumor heterogeneity and the immunosuppressive nature of the tumor microenvironment can limit the durability of the response [Source: Cell, 2021].

Other names

Neoepitope-HLA complexTumor-specific neoantigen-MHC complexPersonalized tumor-specific antigenNeoantigen-reactive T-cell receptorTSA-HLA complex

Induction of a de novo or expanded T-cell response against unique tumor mutations by presenting synthetic or endogenous neoantigens on HLA molecules to be recognized by specific T-cell receptors, leading to targeted tumor cell lysis [Source: Nature Reviews Cancer, 2017].