Restriction of PD-1 function by cis -PD-L1/CD80 interactions is required for optimal T cell responses

Abstract

Targeted blockade of PD-1 with immune checkpoint inhibitors can activate T cells to destroy tumors. PD-1 is believed to function mainly at the effector, but not in the activation, phase of T cell responses, yet how PD-1 function is restricted at the activation stage is currently unknown. Here we demonstrate that CD80 interacts with PD-L1 in cis on antigen-presenting cells (APCs) to disrupt PD-L1/PD-1 binding. Subsequently, PD-L1 cannot engage PD-1 to inhibit T cell activation when APCs express substantial amounts of CD80. In knock-in mice in which cis-PD-L1/CD80 interactions do not occur, tumor immunity and autoimmune responses were greatly attenuated by PD-1. These findings indicate that CD80 on APCs limits the PD-1 coinhibitory signal, while promoting CD28-mediated costimulation, and highlight critical components for induction of optimal immune responses.

VISTA: Coming of age as a multi-lineage immune checkpoint

“…From a translational standpoint, the authors introduced novel pH‐dependent anti‐VISTA antibodies, but showed neither a therapeutic advantage of these clones over the ‘conventional’ anti‐VISTA antagonists nor a reduction in adverse events. Based on recent findings of PD‐L1 cis ‐interactions with CD80 on myeloid cells and its profound functions in regulating immunity , and the very similar of PSGL1 and VISTA expression on the same leukocyte populations, one can reasonably hypothesize that these two proteins may be interacting (in cis ) on the same cell‐forming heterodimers and may both be required for co‐signalling in some contexts. Utilization of available VISTA‐deficient and PSGL‐1‐deficient mice could readily address these questions.…”

A tissue-like platform for studying engineered quiescent human T-cells’ interactions with dendritic cells

“…This has also been corroborated by enhanced activation, although only observable for late readouts such as 41BB expression and target cell killing (Figure 5D). Interestingly we saw an enhanced expression of PDL-1 (Figure 5- Supplement Figure 1B), the ligand for PD-1, on CD8 T-cells, which could lead to cis interactions that act as a cell intrinsic regulation mechanism 25 . Surprisingly, we noted that there are differences between the pathways enhanced by the two blocking antibody clones where EH12 seems superior at enhancing surface markers, whereas Nivolumab outperforms EH12 in the killing assays.…”

A novel system to map protein interactions reveals evolutionarily conserved immune evasion pathways on transmissible cancers

“…In humans, overexpression of some checkpoint proteins can block surface expression of heterophilic binding partners in cis (e.g. CD80 and PDL1) 42, 43 . As a potential route for disrupting the inhibitory effects of CD200 on anti-tumor immunity, we tested if overexpression of CD200R1 on DFT cells could reduce CD200 surface expression.…”