PD-1 signaling negatively regulates the common cytokine receptor γ chain via MARCH5-mediated ubiquitination and degradation to suppress anti-tumor immunity

Abstract

Combination therapy with PD-1 blockade and IL-2 substantially improves anti-tumor efficacy comparing to monotherapy. The underlying mechanisms responsible for the synergistic effects of the combination therapy remain enigmatic. Here we show that PD-1 ligation results in BATF-dependent transcriptional induction of the membrane-associated E3 ubiquitin ligase MARCH5, which mediates K27-linked polyubiquitination and lysosomal degradation of the common cytokine receptor γ chain (γc). PD-1 ligation also activates SHP2, which dephosphorylates γcY357, leading to impairment of γc family cytokine-triggered signaling. Conversely, PD-1 blockade restores γc level and activity, thereby sensitizing CD8+ T cells to IL-2. We also identified Pitavastatin Calcium as an inhibitor of MARCH5, which combined with PD-1 blockade and IL-2 significantly improves the efficacy of anti-tumor immunotherapy in mice. Our findings uncover the mechanisms by which PD-1 signaling antagonizes γc family cytokine-triggered immune activation and demonstrate that the underlying mechanisms can be exploited for increased efficacy of combination immunotherapy of cancer.

PD-1-mediated inhibition of T cell activation: Mechanisms and strategies for cancer combination immunotherapy

“…These results point to a model on the regulatory mechanisms of γ c stability and activity by PD-1 signaling ( Liu et al, 2023 ). PD-1 ligation promotes the interaction between SHP-2 and γ c .…”

“…PD-L1-induced up-regulation of MARCH5 mRNA and down-regulation of γ c protein level is inhibited in BATF-deficient cells. These studies suggest that PD-1 ligation results in BATF-dependent transcriptional induction of the E3 ubiquitin ligase MARCH5, leading to K27-linked polyubiquitination and lysosomal degradation of γ c ( Liu et al, 2023 ).…”

“…Previous studies have shown that PD-1 mediates inhibition of PI3K-AKT pathway and Ras-MEK-ERK pathway ( Parry et al, 2005 ; Patsoukis et al, 2012 ; Sheppard et al, 2004 ). PD-1 signal can also antagonize γ c family cytokine-mediated immune activation by directly targeting γ c ( Liu et al, 2023 ).…”

“…PD-1-induced inhibition of γ c -mediated signaling and immune activation is also regulated by SHP-2 ( Liu et al, 2023 ). PD-1 ligation triggers clustering of PD-1 with dynamic TCR microclusters which is necessary for the recruitment of SHP-2 and accumulates at the signaling central supramolecular activation cluster (c-SMAC) ( Boussiotis, 2016 ; Patsoukis et al, 2020 ; Xu et al, 2020 ).…”

“…Previous studies have demonstrated that T cell costimulatory receptor CD28 is a target for PD-1-mediated inhibition, which is not a TCR-associated component ( Hui et al, 2017 ). A recent study has also shown that PD-1 ligation-triggered SHP-2 activation induces dephosphorylation of γ c Y357 , resulting in desensitization of γ c -mediated signaling and immune activation ( Liu et al, 2023 ). SHP-2-deficency impairs PD-1 ligation-induced γ c Y357 dephosphorylation and increases the γ c family cytokine-induced phosphorylation of γ c Y357 .…”