T Cell Receptor Chain Centricity: The Phenomenon and Potential Applications in Cancer Immunotherapy

T cells are crucial players in adaptive anti-cancer immunity. The gene modification of T cells with tumor antigen-specific T cell receptors (TCRs) was a milestone in personalized cancer immunotherapy. TCR is a heterodimer (either α/β or γ/δ) able to recognize a peptide antigen in a complex with self-MHC molecules. Although traditional concepts assume that an α- and β-chain contribute equally to antigen recognition, mounting data reveal that certain receptors possess chain centricity, i.e., one hemi-chain TCR dominates antigen recognition and dictates its specificity. Chain-centric TCRs are currently poorly understood in terms of their origin and the functional T cell subsets that express them. In addition, the ratio of α- and β-chain-centric TCRs, as well as the exact proportion of chain-centric TCRs in the native repertoire, is generally still unknown today. In this review, we provide a retrospective analysis of studies that evidence chain-centric TCRs, propose patterns of their generation, and discuss the potential applications of such receptors in T cell gene modification for adoptive cancer immunotherapy.