Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory

TLDR

PD‑L1 expressed on tumor cells binds PD‑1 on T cells to suppress their activity, and antibody blockade of PD‑L1 can elicit durable anti‑tumor responses in some patients. The study investigates a novel PD‑L1 mechanism whereby tumor‑derived exosomes carry PD‑L1 to modulate immune activity. Eliminating exosomal PD‑L1 suppresses tumor growth even in antibody‑resistant models, dampens T‑cell activation in draining lymph nodes, and works synergistically with anti‑PD‑L1 antibodies, indicating exosomal PD‑L1 as a promising therapeutic target to overcome resistance.

Abstract

PD-L1 on the surface of tumor cells binds its receptor PD-1 on effector T cells, thereby suppressing their activity. Antibody blockade of PD-L1 can activate an anti-tumor immune response leading to durable remissions in a subset of cancer patients. Here, we describe an alternative mechanism of PD-L1 activity involving its secretion in tumor-derived exosomes. Removal of exosomal PD-L1 inhibits tumor growth, even in models resistant to anti-PD-L1 antibodies. Exosomal PD-L1 from the tumor suppresses T cell activation in the draining lymph node. Systemically introduced exosomal PD-L1 rescues growth of tumors unable to secrete their own. Exposure to exosomal PD-L1-deficient tumor cells suppresses growth of wild-type tumor cells injected at a distant site, simultaneously or months later. Anti-PD-L1 antibodies work additively, not redundantly, with exosomal PD-L1 blockade to suppress tumor growth. Together, these findings show that exosomal PD-L1 represents an unexplored therapeutic target, which could overcome resistance to current antibody approaches.