Poggio et al. observed high PD-L1 levels in exosomes secreted from prostate cancer cell lines, which increased upon IFNγ stimulation. CRISPR knockouts of Rab27a or nSMase2, each involved in exosome formation, decreased PD-L1 secretion. Mice injected with Rab27a-/- or PD-L1-/- TRAMP-C2 prostate cancer cells did not develop tumors and displayed a higher CD8+ T cell fraction in draining lymph nodes, reduced T cell inhibitory marker expression, and slowed growth of a second wildtype tumor injected either at a later timepoint or simultaneously on the opposite flank. Intravenous injection of cancer-derived exosomes restored immunosuppression.
Contributed by Alex Najibi
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.