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Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory
- Poggio, Mauro, Hu, Tianyi, Pai, Chien-Chun, Chu, Brandon, Belair, Cassandra D., Chang, Anthony, Montabana, Elizabeth, Lang, Ursula E., Fu, Qi, Fong, Lawrence, Blelloch, Robert
- Cell 2019 v.177 no.2 pp. 414-427.e13
- T-lymphocytes, antibodies, exosomes, immune response, lymph nodes, models, neoplasm cells, neoplasms, patients, secretion, therapeutics
- 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.