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-Ll 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 posi-tively correlated with the expression of heterogeneous nuclear ribonucleoprotein L(HnRNP L).Hence,we further investigated the potential role of HnRNP 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,HnRNP 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,HnRNP 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 HnRNP L promoted the cancer immune escape partly through tar-geting YY1/PD-L1 axis and inhibiting ferroptosis in CRPC cells.Furthermore,HnRNP L knockdown enhanced antitumor immunity by recruiting infiltrating CD8+T cells and synergized with anti-PD-1 ther-apy in CRPC tumors.This study provided biological evidence that HnRNP L knockdown might be a novel therapeutic agent in PD-L1/PD-1 blockade strategy that enhanced anti-tumor immune response in CRPC.

Xumin Zhou;Libin Zou;Hangyu Liao;Junqi Luo;Taowei Yang;Jun Wu;Wenbin Chen;Kaihui Wu;Shengren Cen;Daojun Lv;Fangpeng Shu;Yu Yang;Chun Li;Bingkun Li;Xiangming Mao

Department of Urology,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China;Second Department of Hepatobiliary Surgery,Zhujiang Hospital,Southern Medical University,Guangzhou 510280,China;Department of Urology,Minimally Invasive Surgery Center,the First Affiliated Hospital of Guangzhou Medical University,Guangzhou 510120,China;Department of Urology,Guangzhou Women and Children's Medical Center,Guangzhou Medical University,Guangzhou 510623,China;Department of Urology,Peking University Shenzhen Hospital,Shenzhen 518036,China;Nursing Department,Nanfang Hospital,Southern Medical University,Guangzhou 510515,China

药学学报（英文版）

[1]Xumin Zhou;Libin Zou;Hangyu Liao;Junqi Luo;Taowei Yang;Jun Wu;Wenbin Chen;Kaihui Wu;Shengren Cen;Daojun Lv;Fangpeng Shu;Yu Yang;Chun Li;Bingkun Li;Xiangming Mao-.Abrogation of HnRNP L enhances anti-PD-1 therapy efficacy via diminishing PD-L1 and promoting CD8+T cell-mediated ferroptosis in castration-resistant prostate cancer)[J].药学学报（英文版）,2022(02):692-707

Abrogation,HnRNP

enhances,efficacy,via,diminishing,L1,promoting,CD8+T,mediated,ferroptosis,castration,resistant,prostate,Owing,incurable,CRPC,ultimately,developing,after,treating,androgen,deprivation,ADT,vital,devise,new,therapeutic,strategies,Treatments,that,programmed,death,ligand,have,been,approved,human,cancers,clinical,benefit,However,many,patients,especially,fail,respond,Ll,treatment,so,urgent,need,seek,support,strategy,improving,traditional,targeting,immunotherapy,present,study,analyzing,data,from,our,tissue,microarray,found,was,correlated,heterogeneous,nuclear,ribonucleoprotein,Hence,further,investigated,potential,role,sensitivity,cells,killing,synergistic,Indeed,knockdown,effectively,decreased,recovered,vitro,vivo,contrary,overexpression,opposite,addition,consistent,previous,revealed,played,critical,induced,promoted,immune,escape,partly,through,YY1,axis,inhibiting,Furthermore,enhanced,antitumor,immunity,by,recruiting,infiltrating,synergized,tumors,This,provided,biological,evidence,might,novel,agent,blockade,response

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