Engineering T cells with a novel PD-L1-specific TCR targeting immune and cancer cells

The immune system plays a central role in recognizing and eliminating cancer cells, yet many tumors escape immune surveillance by creating an immunosuppressive microenvironment driven by inhibitory cytkines, checkpoint molecules and tolerogenic immune cell subsets. Reversing this suppression has been pursued therapeutically, most notably through blockade of immune checkpoints such as the PD-1/PD-L1 axis. Complementing these approaches, our research group has identified naturally occurring proinflammatory T cells that recognize tumor microenvironment (TME) antigens expressed by key immunosuppressive cells in the TME. 1 Among these, PD-L1-specific T cells were detected in both healthy donors and cancer patients and were able to eliminate PD-L1-expressing tumor and immune cells, highlighting their immune modulatory potential. 2 Importantly, their therapeutic relevance was demonstrated in a clinical trial where vaccination with PD-L1- and indoleamine 2,3-dioxygenase (IDO)-derived peptides combined with PD-1 blockade achieved high response rates in patients with metastatic melanoma. 3