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 (γ_c). PD-1 ligation also activates SHP2, which dephosphorylates γ_c^Y357, leading to impairment of γ_c family cytokine-triggered signaling. Conversely, PD-1 blockade restores γ_c level and activity, thereby sensitizing CD8⁺ T cells to IL-2. We also identified

SUBMITTER: Liu R 

PROVIDER: S-EPMC10709454 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature