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

Cell. 2019 Apr 4;177(2):414-427.e13. doi: 10.1016/j.cell.2019.02.016.


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.

Keywords: CD274; NSMASE2; PD-L1; RAB27A; SMPD3; T cells; abscopal; cancer; exosomes; immune checkpoint.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / therapeutic use
  • B7-H1 Antigen / metabolism*
  • B7-H1 Antigen / physiology*
  • Cell Line, Tumor
  • Exosomes / metabolism
  • Humans
  • Immunotherapy
  • Lymphocyte Activation / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • T-Lymphocytes / immunology
  • Tumor Microenvironment / immunology*
  • Tumor Microenvironment / physiology


  • Antibodies, Monoclonal
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Programmed Cell Death 1 Receptor