Docetaxel remodels prostate cancer immune microenvironment and enhances checkpoint inhibitor-based immunotherapy

Theranostics. 2022 Jun 27;12(11):4965-4979. doi: 10.7150/thno.73152. eCollection 2022.

Abstract

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.

Keywords: Docetaxel; Immune microenvironment; Immunotherapy; Prostate Cancer; cGAS/STING.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Disease Models, Animal
  • Docetaxel / therapeutic use
  • Humans
  • Immunologic Factors
  • Immunotherapy* / methods
  • Male
  • Mice
  • Nucleotidyltransferases
  • Prostatic Neoplasms* / drug therapy
  • Retrospective Studies
  • Tumor Microenvironment

Substances

  • Immunologic Factors
  • Docetaxel
  • Nucleotidyltransferases