Division of Molecular Oncology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.
Proteomics Core Facility, The Netherlands Cancer Institute, Plesmanlaan 121, 1066, CX, Amsterdam, The Netherlands.
Nat Commun. 2022 Apr 8;13(1):1923. doi: 10.1038/s41467-022-29442-x.
The cytokine IFNγ differentially impacts on tumors upon immune checkpoint blockade (ICB). Despite our understanding of downstream signaling events, less is known about regulation of its receptor (IFNγ-R1). With an unbiased genome-wide CRISPR/Cas9 screen for critical regulators of IFNγ-R1 cell surface abundance, we identify STUB1 as an E3 ubiquitin ligase for IFNγ-R1 in complex with its signal-relaying kinase JAK1. STUB1 mediates ubiquitination-dependent proteasomal degradation of IFNγ-R1/JAK1 complex through IFNγ-R1 and JAK1. Conversely, STUB1 inactivation amplifies IFNγ signaling, sensitizing tumor cells to cytotoxic T cells in vitro. This is corroborated by an anticorrelation between STUB1 expression and IFNγ response in ICB-treated patients. Consistent with the context-dependent effects of IFNγ in vivo, anti-PD-1 response is increased in heterogenous tumors comprising both wildtype and STUB1-deficient cells, but not full STUB1 knockout tumors. These results uncover STUB1 as a critical regulator of IFNγ-R1, and highlight the context-dependency of STUB1-regulated IFNγ signaling for ICB outcome.
细胞因子 IFNγ 在免疫检查点阻断（ICB）时对肿瘤的影响不同。尽管我们了解下游信号事件，但对于其受体（IFNγ-R1）的调节知之甚少。通过对 IFNγ-R1 细胞表面丰度的关键调节因子进行无偏见的全基因组 CRISPR/Cas9 筛选，我们发现 STUB1 是与信号转导激酶 JAK1 形成复合物的 IFNγ-R1 的 E3 泛素连接酶。STUB1 通过 IFNγ-R1 和 JAK1 介导 IFNγ-R1/JAK1 复合物的泛素化依赖性蛋白酶体降解。相反，STUB1 的失活会放大 IFNγ 信号，使肿瘤细胞在体外对细胞毒性 T 细胞敏感。这在接受 ICB 治疗的患者中，STUB1 表达与 IFNγ 反应之间的反相关得到了证实。与 IFNγ 在体内的上下文相关效应一致，包含野生型和 STUB1 缺陷型细胞的异质性肿瘤中抗 PD-1 反应增加，但在完全 STUB1 敲除肿瘤中没有增加。这些结果揭示了 STUB1 是 IFNγ-R1 的关键调节因子，并强调了 STUB1 调节的 IFNγ 信号对 ICB 结果的上下文依赖性。
