Abrogation of Hn RNP L enhances anti-PD-1 therapy efficacy via diminishing PD-L1 and promoting CD8^(+) T cell-mediated ferroptosis in castration-resistant prostate cancer

查看全文 作　　者：Xumin [1]Zhou;Libin [1]Zou;Hangyu [2]Liao;Junqi [1]Luo;Taowei [1]Yang;Jun [1]Wu;Wenbin [1]Chen;Kaihui [1]Wu;Shengren [1]Cen;Daojun [4]Lv;Fangpeng [5]Shu;Yu [6]Yang;Chun [3]Li;Bingkun [1]Li;Xiangming [1]Mao

机构地区：[1]Department of Urology,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China;[2]Second Department of Hepatobiliary Surgery,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China;[3]Nursing Department,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China;[4]Department of Urology,Minimally Invasive Surgery Center,the First Affiliated Hospital of Guangzhou Medical University,Guangzhou 510120,China;[5]Department of Urology,Guangzhou Women and Children’s Medical Center,Guangzhou Medical University,Guangzhou 510623,China;[6]Department of Urology,Peking University Shenzhen Hospital,Shenzhen 518036,China

出　　处：《Acta Pharmaceutica Sinica B》索引2022年第12卷第2期,共16页

基　　金：supported by the National Natural Science Foundation of China(Grant No.81773277);Science and Technology Program of Guangzhou,China(Grant No.201803010014);Guangdong Basic and Applied Basic Research Foundation(Grant Nos.2020A1515110922 and 2019A1515110033,China);China Postdoctoral Science Foundation funded project(Grant Nos.2018M643126 and 2019M662865);Distinguished Young Talents in Higher Education Foundation of Guangdong Province(Grant No.2019KQNCX115,China);Achievement Cultivation and Clinical Transformation Application Cultivation Projects of the First Affiliated Hospital of Guangzhou Medical University(Grant No.ZH201908,China)。 摘　　要：Owing to incurable castration-resistant prostate cancer(CRPC)ultimately developing after treating with androgen deprivation therapy(ADT),it is vital to devise new therapeutic strategies to treat CRPC.Treatments that target programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for human cancers with clinical benefit.However,many patients,especially prostate cancer,fail to respond to anti-PD-1/PD-L1 treatment,so it is an urgent need to seek a support strategy for improving the traditional PD-1/PD-L1 targeting immunotherapy.In the present study,analyzing the data from our prostate cancer tissue microarray,we found that PD-L1 expression was positively correlated with the expression of heterogeneous nuclear ribonucleoprotein L(Hn RNP L).Hence,we further investigated the potential role of Hn RNP L on the PD-L1 expression,the sensitivity of cancer cells to T-cell killing and the synergistic effect with anti-PD-1 therapy in CRPC.Indeed,Hn RNP L knockdown effectively decreased PD-L1 expression and recovered the sensitivity of cancer cells to T-cell killing in vitro and in vivo,on the contrary,Hn RNP L overexpression led to the opposite effect in CRPC cells.In addition,consistent with the previous study,we revealed that ferroptosis played a critical role in T-cell-induced cancer cell death,and Hn RNP L promoted the cancer immune escape partly through targeting YY1/PD-L1 axis and inhibiting ferroptosis in CRPC cells.Furthermore,Hn RNP L knockdown enhanced antitumor immunity by recruiting infiltrating CD8^(+)T cells and synergized with anti-PD-1 therapy in CRPC tumors.This study provided biological evidence that Hn RNP L knockdown might be a novel therapeutic agent in PD-L1/PD-1 blockade strategy that enhanced anti-tumor immune response in CRPC. 关键词：HnRNP L PD-L1 YY1 Ferroptosis Immune escape Immune checkpoint blockade Anti-PD-1 therapy Castration-resistant prostate cancer

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Abrogation of Hn RNP L enhances anti-PD-1 therapy efficacy via diminishing PD-L1 and promoting CD8^(+) T cell-mediated ferroptosis in castration-resistant prostate cancer

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