Host self-peptide–Human Leukocyte Antigen complex (self-pHLA) (self-pHLA)

Host self-peptide–Human Leukocyte Antigen (HLA) complexes are molecular assemblies consisting of an HLA molecule and a short peptide fragment derived from the host's own proteome. These complexes are displayed on the cell surface to be surveyed by T-cells, playing a critical role in establishing central and peripheral immune tolerance [1]. In healthy states, the immune system is trained to ignore these self-complexes; however, in autoimmune diseases such as Type 1 diabetes or Multiple Sclerosis, specific self-pHLA complexes are erroneously recognized by autoreactive T-cells, leading to tissue destruction [2]. In oncology, certain self-antigens, such as cancer-testis antigens or lineage-specific antigens, are overexpressed in tumors, making their HLA-presented peptides viable targets for immunotherapy [3]. Modern therapeutic approaches include TCR-mimic antibodies, bispecific T-cell engagers like Tebentafusp, and engineered TCR-T cell therapies like Afamitresgene autoleucel, which specifically bind these complexes to redirect immune responses [3,4]. These therapies allow for the targeting of intracellular proteins that are otherwise inaccessible to traditional antibody-based drugs. Safety concerns primarily involve "off-target, on-organ" toxicity, where the therapeutic cross-reacts with similar self-peptides presented on vital healthy tissues [4].

Other names

Self-peptide–MHC complexAutologous peptide–HLA complexMHC-restricted self-antigenpMHCSelf-pHLA

Therapeutic agents target these complexes using engineered T-cell receptors (TCRs) or TCR-mimic antibodies to induce selective cell lysis in cancer, or aim to modulate T-cell recognition to restore tolerance in autoimmune conditions [3,4].