Identification of a tumor-specific allo-HLA–restricted gdTCR

gdT cells are key players in cancer immune surveillance because of their ability to recognize malignant transformed cells, which makes them promising therapeutic tools in the treatment of cancer. However, the biological mechanisms of how gdT-cell receptors (TCRs) interact with their ligands are poorly understood. Within this context, we describe the novel allo-HLA–restricted and CD8a-dependent Vg5Vd1TCR. In contrast to the previous assumption of the general allo-HLA reactivity of a minor fraction of gdTCRs, we show that classic anti-HLA–directed, gdTCR-mediated reactivity can selectively act on hematological and solid tumor cells, while not harming healthy tissues in vitro and in vivo. We identified the molecular interface with proximity to the peptide-binding groove of HLA-A*24:02 as the essential determinant for recognition and describe the critical role of CD8 as a coreceptor. We conclude that alloreactive gdT-cell repertoires provide therapeutic opportunities, either within the context of haplotransplantation or as individual gdTCRs for genetic engineering of tumor-reactive T cells.