Tumor-derived peptide–HLA class I complex (pHLA-I)

Tumor-derived peptide–HLA class I complexes are specialized molecular structures on the surface of malignant cells that present intracellular protein fragments to the immune system. These complexes are formed when degraded proteins, including mutated neoantigens or overexpressed tumor-associated antigens, are loaded onto Human Leukocyte Antigen (HLA) class I molecules within the endoplasmic reticulum and subsequently transported to the cell membrane [1]. They serve as the primary "identity tags" that allow CD8+ cytotoxic T lymphocytes to distinguish cancerous cells from healthy ones through specific T-cell receptor (TCR) binding [2]. In oncology, these complexes are highly sought-after therapeutic targets because they provide access to the intracellular proteome, which contains many more potential targets than the cell surface [3]. Current therapeutic modalities include TCR-engineered T-cell therapies (TCR-T) and bispecific T-cell engagers, such as ImmTACs, which are designed to bypass the limitations of traditional monoclonal antibodies [4]. However, the clinical utility of targeting these complexes is often restricted by the requirement for patients to possess specific HLA alleles and the risk of "off-target, on-organ" toxicity if the target peptide is shared by healthy tissues [5]. Citations: [1] Rock KL, et al. (2016). "Present Yourself: Mechanisms of Antigen Presentation." Cell. [2] Hennecke J, Wiley DC. (2001). "T cell receptor-MHC interactions up close." Cell. [3] Dao T, Scheinberg DA. (2013). "Therapeutic antibodies to intracellular receptors." Expert Opinion on Therapeutic Targets. [4] Middleton MR, et al. (2022). "Tebentafusp: A First-in-Class TCR-Based Therapy." New England Journal of Medicine. [5] Linette GP, et al. (2013). "Cardiovascular toxicity and titin cross-reactivity of TCR-engineered T cells." Blood.

Other names

Peptide-MHC class I complexpMHC-ITumor-associated antigen-HLA complexNeoantigen-HLA complexpMHC

Recognition by T-cell receptors (TCRs) or TCR-mimetic antibodies to trigger cytotoxic T-lymphocyte-mediated lysis of malignant cells.