Cell-intrinsic PD-L1 ablation sustains effector CD8+ T cell responses and promotes antitumor T cell therapy

Adoptive cell therapies are emerging forms of immunotherapy that reprogram T cells for enhanced antitumor responses. Although surface programmed cell death-ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) engagement inhibits antitumor immunity, the role of cell-intrinsic PD-L1 in adoptive T cell therapy remains unknown. Here, we found that intracellular PD-L1 was enriched in tumor-infiltrating CD8+ T cells of cancer patients. PD-L1 ablation promoted antitumor immune responses and the maintenance of an effector-like state of therapeutic CD8+ T cells, while blockade of surface PD-L1 was unable to impact on their expansion and function. Moreover, cell-intrinsic PD-L1 impeded CD8+ T cell activity, which partially relied on mTORC1 signaling. Furthermore, endogenous tumor-reactive CD8+ T cells were motivated by BATF3-driven dendritic cells after adoptive transfer of PD-L1-deficient therapeutic CD8+ T cells. This role of cell-intrinsic PD-L1 in therapeutic CD8+ T cell dysfunction highlights that disrupting cell-intrinsic PD-L1 in CD8+ T cells represents a viable approach to improving T cell-based cancer immunotherapy. [Display omitted] •Intracellular PD-L1 could dampen adaptive antitumor immune responses•PD-L1 deficiency promotes the maintenance of effector-like state of therapeutic CD8+ T cells•PD-L1 deficiency augments CD8+ T cell activity via mTORC1-mediated metabolic reprogramming•Therapeutic PD-L1-/- CD8+ T cells boosts endogenous CD8+ T cell function through CD103+ DCs Wang et al. demonstrate that intracellular PD-L1 deficiency enhanced the antitumor response of therapeutic CD8+ T cells. These results highlight a role for PD-L1 in the dysfunction of tumor-infiltrating CD8+ T cells and provide an informative theoretical basis for the development of T cell-based immunotherapies by targeting cell-intrinsic PD-L1.