期刊
THERANOSTICS
卷 12, 期 11, 页码 4965-4979出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.73152
关键词
Prostate Cancer; Docetaxel; cGAS/STING; Immunotherapy; Immune microenvironment
资金
- National Natural Science Foundation of China [82172868, 81972578, 82072847, 81772742]
- Science and Technology Commission of Shanghai Municipality [19XD140 2300]
- Shanghai Municipal Health Commission [2019LJ11, 2020CXJQ03]
- Shanghai Shenkang Hospital Development Center [SHDC2020CR6008, 16CR30 49A]
- Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning [TP2017029]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support [20191906, 20171912, 20152215]
This study found that docetaxel-based chemohormonal therapy activates the immune response in prostate cancer and facilitates T cell infiltration, thereby improving the efficacy of anti-PD1 blockade therapy.
Background: Prostate cancer is usually considered as immune cold tumor with poor immunogenic response and low density of tumor-infiltrating immune cells, highlighting the need to explore clinically actionable strategies to sensitize prostate cancer to immunotherapy. In this study, we investigated whether docetaxel-based chemohormonal therapy induces immunologic changes and potentiates checkpoint blockade immunotherapy in prostate cancer. Methods: We performed transcriptome and histopathology analysis to characterize the changes of prostate cancer immune microenvironment before and after docetaxel-based chemohormonal therapy. Furthermore, we investigated the therapeutic benefits and underlying mechanisms of chemohormonal therapy combined with anti-PD1 blockade using cellular experiments and xenograft prostate cancer models. Finally, we performed a retrospective cohort analysis to evaluate the antitumor efficacy of anti-PD1 blockade alone or in combination with docetaxel-based chemotherapy. Results: Histopathology assessments on patient samples confirmed the enrichment of tumor-infiltrating T cells after chemohormonal therapy. Moreover, we found that docetaxel activated the cGAS/STING pathway in prostate cancer, subsequently induced IFN signaling, resulting in lymphocytes infiltration. In a xenograft mouse model, docetaxel-based chemohormonal therapy prompted the intratumoral infiltration of T cells and upregulated the abundance of PD1 and PD-L1, thereby sensitizing mouse tumors to the anti-PD1 blockade. To determine the clinical significance of these results, we retrospectively analyzed a cohort of 30 metastatic castration-resistant prostate cancer patients and found that docetaxel combined with anti-PD1 blockade resulted in better prostate-specific antigen progression-free survival when compared with anti-PD1 blockade alone. Conclusions: Our study demonstrates that docetaxel activates the antitumoral immune response and facilitates T cell infiltration in a cGAS/STING-dependent manner, providing a combination immunotherapy strategy that would improve the clinical benefits of immunotherapy.
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