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

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 gamma chain (gamma c). PD-1 ligation also activates SHP2, which dephosphorylates gamma cY357, leading to impairment of gamma c family cytokine-triggered signaling. Conversely, PD-1 blockade restores gamma c 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 gamma c family cytokine-triggered immune activation and demonstrate that the underlying mechanisms can be exploited for increased efficacy of combination immunotherapy of cancer.

Automated summary

Combination therapy with PD-1 blockade and IL-2 improves anti-tumor efficacy, but the underlying mechanisms are not well understood. Our study reveals that PD-1 blockade enhances IL-2 effect by regulating the MARCH5 and γc signaling pathways, leading to potential benefits in cancer immunotherapy.