PD-L1:CD80 Heterodimer Triggers CD28 While Repressing Both PD-1 and CTLA4 Pathways

Combined immunotherapy with anti-PD-1/PD-L1 and anti-CTLA4 has resulted in superior clinical responses compared to single agent therapy. The underlying mechanisms for this synergy have yet to be elucidated and investigations have largely focused on cellular interactions. Herein, we report a molecular crosstalk in which the PD-1 ligand PD-L1 and the CTLA4 ligand CD80 heterodimerize in cis. This heterodimerization blocks both PD-L1:PD-1 and CD80:CTLA4 interactions, but preserves the ability of CD80 to activate the T cell costimulatory receptor CD28. Remarkably, PD-L1 expression on antigen presenting cells (APCs) protects CD80 from CTLA4 mediated trans-endocytosis, and the therapeutic PD-L1 blockade antibody atezolizumab paradoxically downregulates CD80 on APCs, presumably reducing its co-stimulatory ability. Importantly, this effect can be negated by co-blockade of CTLA4 with ipilimumab. Our study reveals an unexpected immune stimulatory role of cis-acting PD-L1 and a mechanism of anti-PD-L1/anti-CTLA4 crosstalk, providing a therapeutic rationale for combination blockade of PD-L1 and CTLA4.