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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

引用

Acta Pharmaceutica Sinica B 2022年第2期12卷 692-707页

作者： 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 HospitalSouthern Medical UniversityGuangzhou 510280China Second Department of Hepatobiliary Surgery Zhujiang HospitalSouthern Medical UniversityGuangzhou 510280China Nursing Department Nanfang HospitalSouthern Medical UniversityGuangzhou 510515China Department of Urology Minimally Invasive Surgery Centerthe First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou 510120China Department of Urology Guangzhou Women and Children’s Medical CenterGuangzhou Medical UniversityGuangzhou 510623China Department of Urology Peking University Shenzhen HospitalShenzhen 518036China

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 *** that target programmed cell death protein 1(PD-1)and programmed death ligand-1(PD-L1)have been approved for human cancers with clinical ***,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 *** 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 ***,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 *** 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 ***,Hn RNP L knockdown enhanced antitumor immunity by recruiting infiltrating CD8^(+)T cells and synergized with anti-PD-1 therapy in CRPC *** 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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