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

By M. Poggio, T. Hu, C. Pai, Brandon Chu, Cassandra D. Belair, Anthony A Chang, E. Montabana, U. Lang, Q. Fu, L. Fong and 1 more. Cell, 2019

1,182 citations recorded by the source corpus.

SUMMARY 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.

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/c0dd5663ff62614ac9db42ccbfa3c11f825e9ad6

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In Immunology

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In Molecular Biology

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In Oncology

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Citations in the corpus

• The biology, function, and biomedical applications of exosomes (2020, positive): “Further, cancer cell–derived PD-L1 exosomes promote T cell exhaustion in the draining lymph nodes of tumor-bearingmice, promoting tumorgrowth (84).”
• Mechanisms controlling PD-L1 expression in cancer (2019, background): “Current studies suggest the possibility that both exosomal PD-L1 and sPD-L1 have bioactivity to suppress T-cell immunity systemically (Gong et al., 2019; Poggio et al., 2019; Zhou et al., 2017).”
• The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses (2020, background): “Tumor exosomes can display PD-L1 and bind to PD-1-expressing effector T cells and suppress their activity even in the draining lymph node demonstrating the long distance communication capacity of tumor cells via the release of exosomes (188).”