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

Abstract

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.

Keywords: CD8(+) T cell differentiation; CP: Cancer; CP: Immunology; PD-L1/PD-1; adoptive T cell therapy; tumor immunity.