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.
Author Info: (1) Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edith Broad Institute for Regeneration Medicine, University of California,
Author Info: (1) Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edith Broad Institute for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (2) Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edith Broad Institute for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (3) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (4) Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edith Broad Institute for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (5) Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edith Broad Institute for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (6) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (7) Division of Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. (8) Department of Pathology and Dermatology, University of California, San Francisco, San Francisco, CA 94143, USA. (9) Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edith Broad Institute for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (10) Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA. (11) Department of Urology, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edith Broad Institute for Regeneration Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: robert.blelloch@ucsf.edu.
