Traditional Chinese medicine CFF-1 exerts a potent anti-tumor immunity to hinder tumor growth and metastasis in prostate cancer through EGFR/JAK1/STAT3 pathway to inhibit PD-1/PD-L1 checkpoint signaling

Yu Zhang; Yong Wei; Shun Jiang; Yanmei Dang; Yu Yang; Wenren Zuo; Qingyi Zhu; Ping Liu; Yanhong Gao; Shan Lu

doi:10.1016/j.phymed.2022.153939

Traditional Chinese medicine CFF-1 exerts a potent anti-tumor immunity to hinder tumor growth and metastasis in prostate cancer through EGFR/JAK1/STAT3 pathway to inhibit PD-1/PD-L1 checkpoint signaling

Phytomedicine. 2022 May:99:153939. doi: 10.1016/j.phymed.2022.153939. Epub 2022 Jan 14.

Authors

Yu Zhang¹, Yong Wei², Shun Jiang¹, Yanmei Dang¹, Yu Yang¹, Wenren Zuo², Qingyi Zhu², Ping Liu¹, Yanhong Gao³, Shan Lu⁴

Affiliations

¹ College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu, China.
² Department of Urology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
³ College of Food Science and Pharmacological Engineering, Nanjing Normal University, Nanjing, Jiangsu, China.
⁴ College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu, China. Electronic address: lu_shan@hotmail.com.

PMID: 35172257
DOI: 10.1016/j.phymed.2022.153939

Abstract

Background: Traditional Chinese Medicine (TCM) CFF-1 has been used in clinic for prostate cancer therapy in China. We reported before CFF-1 induced cell apoptosis via suppressing EGFR-related pathways, reminding us its potential role associated with antitumor immunity.

Purpose: The study was aimed to investigate the regulatory mechanism of CFF-1 on PD-L1/PD-1-mediated tumor immune escape.

Methods: Prostate-specific antigen (PSA) test and the functional assessment of cancer therapy-prostate (FACT-P) and karnosky performance status (KPS) questionnaires were carried out to evaluate patient' condition before and after therapy. Flow cytometry (FCM) was used for analyzing cell apoptosis, T lymphocyte subsets and cell cycle. Western blotting and Immunohistochemistry (IHC) were performed to measure protein expressions. The synergy of drug combination was assessed by calculating combination index (CI).

Results: CFF-1 obviously decreased PSA and improved the quality of life in patients with advanced prostate cancer. PD-L1 was highly expressed in prostate cancer cells including LNCaP, 22Rv1, PC-3, DU145 and RM-1. PD-1/PD-L1 was upregulated in tumorigenesis and tumor progression of subcutaneous homograft mouse model with immune response, where CD3+ T cell subsets were declined. CFF-1 inhibited PD-L1 expression in prostate cancer cells in a time/dose-dependent manner and blocked tumor growth by suppressing PD-1/PD-L1 upregulation to promote the recovery of CD3+ T lymphocytes, especially CD4+ T cell subset, accompanied by the downregulation of CD4+ FOXP3+ T cell subset. CFF-1 also prolonged the survival and inhibited lung metastasis in tail vein prostate cancer mouse model while repressing PD-1/PD-L1. CFF-1 in combination with docetaxol (DTX) produced a synergistic effects by sensitizing the inhibitory effect of DTX on JAK1/STAT3 pathway targeting PD-L1 blockade.

Conclusion: CFF-1 inhibited tumor growth and lung metastasis by blocking PD-1/PD-L1 to ameliorate T lymphocyte immune response through EGFR/JAK1/STAT3 pathway, suggesting that CFF-1 might be a promising treatment to resist tumor immunosuppression for prostate cancer patients.

Keywords: Anti-tumor immunity; PD-1/PD-L1; Prostate cancer; T lymphocyte; TCM CFF-1.