Cancer-associated fibroblasts promote enzalutamide resistance and PD-L1 expression in prostate cancer through CCL5-CCR5 paracrine axis

Zhi Xiong; Shun-Li Yu; Zhao-Xiang Xie; Rui-Lin Zhuang; Shi-Rong Peng; Qiong Wang; Ze Gao; Bing-Heng Li; Jun-Jia Xie; Hai Huang; Kai-Wen Li

doi:10.1016/j.isci.2024.109674

Cancer-associated fibroblasts promote enzalutamide resistance and PD-L1 expression in prostate cancer through CCL5-CCR5 paracrine axis

iScience. 2024 Apr 4;27(5):109674. doi: 10.1016/j.isci.2024.109674. eCollection 2024 May 17.

Authors

Zhi Xiong^{1

2}, Shun-Li Yu^{1

2}, Zhao-Xiang Xie^{1

2}, Rui-Lin Zhuang^{1

2}, Shi-Rong Peng^{1

2}, Qiong Wang³, Ze Gao⁴, Bing-Heng Li^{1

2}, Jun-Jia Xie^{1

2}, Hai Huang^{1

2

5

6}, Kai-Wen Li^{1

2}

Affiliations

¹ Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
² Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
³ Department of Urology, Southern Medical University Nanfang Hospital, Guangzhou 510120, China.
⁴ Department of Urology, Qilu Hospital of Shandong University, Jinan 250063, China.
⁵ Guangdong Provincial Clinical Research Center for Urological Diseases, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
⁶ Department of Urology, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Qingyuan 511518, Guangdong, China.

Abstract

Cancer-associated fibroblasts (CAFs) have been shown to play a key role in prostate cancer treatment resistance, but the role of CAFs in the initial course of enzalutamide therapy for prostate cancer remains unclear. Our research revealed that CAFs secrete CCL5, which promotes the upregulation of androgen receptor (AR) expression in prostate cancer cells, leading to resistance to enzalutamide therapy. Furthermore, CCL5 also enhances the expression of tumor programmed death-ligand 1 (PD-L1), resulting in immune escape. Mechanistically, CCL5 binds to the receptor CCR5 on prostate cancer cells and activates the AKT signaling pathway, leading to the upregulation of AR and PD-L1. The CCR5 antagonist maraviroc to inhibit the CAFs mediated CCL5 signaling pathway can effectively reduce the expression of AR and PD-L1, and improve the efficacy of enzalutamide. This study highlights a promising therapeutic approach targeting the CCL5-CCR5 signaling pathway to improve the effectiveness of enzalutamide.

Keywords: Cancer; Cell biology; Microenvironment; Molecular biology.