Antigen-Presenting Cell-Intrinsic PD-1 Neutralizes PD-L1 in cis to Attenuate PD-1 Signaling in 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. [Display omitted] •A subset of tumor cells and infiltrating APCs in NSCLC co-express PD-1 and PD-L1•PD-1 and PD-L1 on the same cell bind in cis with high affinity•PD-1/PD-L1 cis interaction on APCs prevents PD-L1 from triggering T cell PD-1•Selective blockade of tumor intrinsic PD-1 frees up PD-L1 for T cell inhibition Zhao et al. show that the T cell inhibitory receptor PD-1 expressed on tumor cells and tumor-infiltrating APCs neutralizes its ligand, PD-L1, in cis to inhibit canonical PD-1 signaling. Selective blockade of tumor-intrinsic PD-1 frees up tumor PD-L1 for T cell suppression.