Antigen-Presenting Cell-Intrinsic PD-1 Neutralizes PD-L1 in cis to Attenuate PD-1 Signaling in T Cells

Cell Rep. 2018 Jul 10;24(2):379-390.e6. doi: 10.1016/j.celrep.2018.06.054.


The PD-1 pathway, consisting of the co-inhibitory receptor PD-1 on T cells and its ligand (PD-L1) on antigen-presenting cells (APCs), is a major mechanism of tumor immune evasion. PD-1 and PD-L1 blockade antibodies have produced remarkable clinical activities against a subset of cancers. Binding between T cell-intrinsic PD-1 and APC-intrinsic PD-L1 triggers inhibitory signaling to attenuate the T cell response. Here, we report that PD-1 is co-expressed with PD-L1 on tumor cells and tumor-infiltrating APCs. Using reconstitution and cell culture assays, we demonstrate that the co-expressed PD-1 binds to PD-L1 in cis. Such interaction inhibits the ability of PD-L1 to bind T cell-intrinsic PD-1 in trans and, in turn, represses canonical PD-L1/PD-1 inhibitory signaling. Selective blockade of tumor-intrinsic PD-1 frees up tumor-intrinsic PD-L1 to inhibit T cell signaling and cytotoxicity. Our study uncovers another dimension of PD-1 regulation, with important therapeutic implications.

Keywords: PD-1; PD-L1; T cell signaling; cis-interaction; reconstitution; trans-interaction.

Publication types

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

MeSH terms

  • Animals
  • Antigen-Presenting Cells / metabolism*
  • B7-H1 Antigen / metabolism*
  • Cell Line
  • Cell Membrane / metabolism
  • Cytotoxicity, Immunologic
  • Humans
  • Lung Neoplasms / pathology
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Mice
  • Protein Binding
  • Signal Transduction*
  • T-Lymphocytes / metabolism*


  • B7-H1 Antigen