Using in vitro reconstitution of vesicles, cellular reconstitution, and cell culture assays, Zhao et al. found that in antigen-presenting cells (APCs) – including tumor cells – co-expressing PD-1 and PD-L1, the two bind in cis with high affinity, preventing PD-L1 from engaging in trans with T cells. Selective anti-PD-1 antibody blockade of cis signaling between PD-1 and PD-L1 on APCs freed up PD-L1 to engage with T cells and triggered exhaustion. This research indicates that PD-1 negatively regulates PD-L1 in cis and that the net outcome of the PD-1/PD-L1 pathway depends on PD-1 expression on both APCs and T cells.
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.
Author Info: (1) Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. (2) Institute for Molecular Engineerin
Author Info: (1) Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. (2) Institute for Molecular Engineering, University of Chicago, Chicago, IL 60637, USA. (3) Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. (4) Institute for Molecular Engineering, University of Chicago, Chicago, IL 60637, USA; Department of Hepatobiliary Surgery, The First Clinical Medical College of Nanjing Medical University Nanjing, Jiangsu 210029, China. (5) Institute for Molecular Engineering, University of Chicago, Chicago, IL 60637, USA. (6) Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address: enfuhui@ucsd.edu.
