SPOP mutations promote tumor immune escape in endometrial cancer via the IRF1-PD-L1 axis
SPOP mutations promote tumor immune escape in endometrial cancer via the IRF1-PD-L1 axis
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SPOP突变通过IRF1-PD-L1轴促进子宫内膜癌的肿瘤免疫逃逸
DOI：
10.1038/s41418-022-01097-7
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发表时间：
2022-12-08
影响因子：
12.4
通讯作者：
Wan, Xiaoping
中科院分区：
文献类型：
--
作者：
Gao, Kun;Shi, Qing;Wan, Xiaoping
阻断程序性细胞死亡1（PD-1）/程序性细胞死亡1配体（PD-L1）已发展成为癌症患者最有前途的免疫治疗策略之一。肿瘤细胞经常过度表达PD-L1以逃避T细胞介导的免疫监视。然而，驱动癌细胞中PD-L1异常过表达的特定遗传改变仍然知之甚少。编码E3泛素连接酶底物结合接头SPOP的基因在子宫内膜癌（EC）中经常发生突变。在这里，我们报告说，SPOP负调控PD-L1的表达在转录水平。野生型SPOP与IRF 1结合，IRF 1是负责PD-L1诱导型表达的主要转录因子，随后触发其泛素-蛋白酶体降解以抑制IRF 1介导的PD-L1转录上调。相反，EC相关的SPOP突变体失去降解IRF 1的能力，但稳定IRF 1，并上调PD-L1表达。EC相关SPOP突变部分通过增加IRF 1和PD-L1表达加速异种移植肿瘤生长。总之，我们确定SPOP作为IRF 1-PD-L1轴的负调节因子，并表征IRF 1和PD-L1在EC中SPOP突变驱动的肿瘤免疫逃避中的关键作用。
Blockade of programmed cell death 1 (PD-1)/programmed cell death 1 ligand (PD-L1) has evolved into one of the most promising immunotherapy strategies for cancer patients. Tumor cells frequently overexpress PD-L1 to evade T cell-mediated immune surveillance. However, the specific genetic alterations that drive aberrant overexpression of PD-L1 in cancer cells remain poorly understood. The gene encoding the E3 ubiquitin ligase substrate-binding adaptor SPOP is frequently mutated in endometrial cancer (EC). Here, we report that SPOP negatively regulates PD-L1 expression at the transcriptional level. Wild-type SPOP binds to IRF1, a primary transcription factor responsible for the inducible expression of PD-L1, and subsequently triggers its ubiquitin- proteasomal degradation to suppress IRF1-mediated transcriptional upregulation of PD-L1. In contrast, EC-associated SPOP mutants lose their capacity to degrade IRF1 but stabilize IRF1, and upregulate PD-L1 expression. EC-associated SPOP mutations accelerate xenograft tumor growth partially by increasing IRF1 and PD-L1 expression. Together, we identify SPOP as a negative regulator of the IRF1-PD-L1 axis and characterize the critical roles of IRF1 and PD-L1 in SPOP mutation-driven tumor immune evasion in EC.