Nuclear PD-L1 promotes EGR1-mediated angiogenesis and accelerates tumorigenesis
Jie Yu, Ai Zhuang, Xiang Gu, Yu Hua, Ludi Yang, Shengfang Ge, Jing Ruan, Peiwei Chai, Renbing Jia, Xianqun Fan
Abstract
Abstract Targeting programmed cell death protein ligand 1 (PD-L1) remains one of the most essential immunotherapies in cancer 1,2 . PD-L1 has been detected in the nucleus in multiple malignancies, playing an oncogenic role independent of immune checkpoint regulation 3–5 . Howbeit, the regulatory function of nuclear PD-L1 (nPD-L1) remains to be fully understood. Here, we report that nPD-L1 is an endogenous accelerator for cancer angiogenesis. First, we found that an abundant proportion of PD-L1 was distributed within the nucleus of uveal melanoma samples, which is associated with an unfavorable outcome. Moreover, the capacity of promoting angiogenesis was largely attenuated in the nPD-L1-deficient cells both in vivo and in vitro. Mechanistically, nPD-L1 facilitates p-STAT3 binding to the promoter of early growth response-1 ( EGR1 ), resulting in the activation of EGR1-mediated angiogenesis. Therapeutically, the inhibition of histone deacetylase 2 restores the normal acetylation level of PD-L1, blocking its nuclear translocation and thereby attenuating tumor angiogenesis. Conclusively, we reveal that nPD-L1 promotes angiogenesis in malignancies, and provide a novel anti-vascularization strategy through blocking aberrant PD-L1 nuclear translocation for tumor therapy.