1. Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory.
- Author
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Poggio, Mauro, Hu, Tianyi, Pai, Chien-Chun, Chu, Brandon, Belair, Cassandra D, Chang, Anthony, Montabana, Elizabeth, Lang, Ursula E, Fu, Qi, Fong, Lawrence, and Blelloch, Robert
- Subjects
T-Lymphocytes ,Cell Line ,Tumor ,Animals ,Mice ,Inbred C57BL ,Humans ,Mice ,Antibodies ,Monoclonal ,Immunotherapy ,Lymphocyte Activation ,Male ,Exosomes ,Tumor Microenvironment ,Programmed Cell Death 1 Receptor ,B7-H1 Antigen ,CD274 ,NSMASE2 ,PD-L1 ,RAB27A ,SMPD3 ,T cells ,abscopal ,cancer ,exosomes ,immune checkpoint ,Cancer ,5.1 Pharmaceuticals ,2.1 Biological and endogenous factors ,Development of treatments and therapeutic interventions ,Aetiology ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - 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.
- Published
- 2019