PD-L1 on dendritic cells attenuates T cell activation and regulates response to immune checkpoint blockade

Nat Commun. 2020 Sep 24;11(1):4835. doi: 10.1038/s41467-020-18570-x.

Abstract

Immune checkpoint blockade therapies have shown clinical promise in a variety of cancers, but how tumor-infiltrating T cells are activated remains unclear. In this study, we explore the functions of PD-L1 on dendritic cells (DCs), which highly express PD-L1. We observe that PD-L1 on DC plays a critical role in limiting T cell responses. Type 1 conventional DCs are essential for PD-L1 blockade and they upregulate PD-L1 upon antigen uptake. Upregulation of PD-L1 on DC is mediated by type II interferon. While DCs are the major antigen presenting cells for cross-presenting tumor antigens to T cells, subsequent PD-L1 upregulation protects them from killing by cytotoxic T lymphocytes, yet dampens the antitumor responses. Blocking PD-L1 in established tumors promotes re-activation of tumor-infiltrating T cells for tumor control. Our study identifies a critical and dynamic role of PD-L1 on DC, which needs to be harnessed for better invigoration of antitumor immune responses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / metabolism
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism*
  • Cell Line, Tumor
  • Dendritic Cells / immunology*
  • Dendritic Cells / metabolism*
  • Disease Models, Animal
  • Female
  • HEK293 Cells
  • Humans
  • Interferon-gamma / metabolism
  • Lymphocyte Activation*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • T-Lymphocytes, Cytotoxic / immunology
  • Tumor Microenvironment / immunology
  • Up-Regulation

Substances

  • Antigens, Neoplasm
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Interferon-gamma