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SPOP mutations promote tumor immune escape in endometrial cancer via the IRF1-PD-L1 axis.

ABSTRACT: 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.

SUBMITTER: Gao K

PROVIDER: S-EPMC9950446 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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SPOP mutations promote tumor immune escape in endometrial cancer via the IRF1-PD-L1 axis.

Gao Kun K Shi Qing Q Gu Ye Y Yang Wanqi W He Yuanlong Y Lv Zeheng Z Ding Yan Y Cao Wenxin W Wang Chenji C Wan Xiaoping X

Cell death and differentiation 20221208 2

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 canc ...[more]

PMID: 36481790

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SPOP mutations promote tumor immune escape in endometrial cancer via the IRF1-PD-L1 axis.

Publications

SPOP mutations promote tumor immune escape in endometrial cancer via the IRF1-PD-L1 axis.

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