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

2019; Cell Press; Volume: 177; Issue: 2 Linguagem: Inglês

10.1016/j.cell.2019.02.016

1097-4172

Mauro Poggio, Tianyi Hu, Chien-Chun Steven Pai, Brandon Chu, Cassandra D. Belair, Anthony Chang, Elizabeth Montabana, Ursula E. Lang, Qi Fu, Lawrence Fong, Robert Blelloch,

CAR-T cell therapy research

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.