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

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

doi:10.1016/j.apsb.2021.07.016

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

Acta Pharm Sin B. 2022 Feb;12(2):692-707. doi: 10.1016/j.apsb.2021.07.016. Epub 2021 Jul 21.

Authors

Xumin Zhou¹, Libin Zou¹, Hangyu Liao², Junqi Luo¹, Taowei Yang¹, Jun Wu¹, Wenbin Chen¹, Kaihui Wu¹, Shengren Cen¹, Daojun Lv³, Fangpeng Shu⁴, Yu Yang⁵, Chun Li⁶, Bingkun Li¹, Xiangming Mao¹

Affiliations

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 Department of Urology, Minimally Invasive Surgery Center, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
⁴ Department of Urology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
⁵ Department of Urology, Peking University Shenzhen Hospital, Shenzhen 518036, China.
⁶ Nursing Department, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.

Abstract

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 (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 targeting 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 therapy 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.

Keywords: ADT, androgen deprivation therapy; Anti-PD-1 therapy; CRPC, castration-resistant prostate cancer; Castration-resistant prostate cancer; DMSO, dimethyl sulfoxide; ELISA, enzyme-linked immunosorbent assay; FBS, fetal bovine serum; Fer-1, ferrostatin-1; Ferroptosis; GSH, glutathione; HnRNP L; HnRNP L, heterogeneous nuclear ribonucleoprotein L; IL, interleukin; INF-γ, interferon gamma; Immune checkpoint blockade; Immune escape; PD-1, programmed cell death protein 1; PD-L1; PD-L1, programmed death ligand1; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; YY1; qRT-PCR, quantitative reverse transcription polymerase chain reaction.