Suppression of prostate cancer and amelioration of the immunosuppressive tumor microenvironment through selective immunoproteasome inhibition

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2023
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OncoImmunology. Taylor & Francis. 2023, 12(1), 2156091. ISSN 2162-4011. eISSN 2162-402X. Available under: doi: 10.1080/2162402X.2022.2156091
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New treatment options to battle hormone-refractory prostate carcinoma (PC) are a pressing medical need. Chronic inflammation has been implicated in PC etiology. The pro-inflammatory cytokines IL-6, IL-23 and IL-17 are key mediators to promote growth of PC. Here, we evaluate the potential of immunoproteasome inhibition for anti-inflammatory and direct anti-tumorigenic therapy of PC. The anti-tumor effect of immunoproteasome inhibitor ONX 0914 was tested in mouse and human PC cells and the in vivo therapeutic efficacy of immunoproteasome inhibition was analyzed in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice in preventive and therapeutic settings and in castration-resistant (CR)PC after castration. Inhibition of the immunoproteasome subunit LMP7 induced apoptotic cell death in PC cell lines. In TRAMP mice, ONX 0914-treatment resulted in significant inhibition of PC growth with a decreased frequency of malignant prostatic lesions and inhibition of metastasis formation. The number of immunosuppressive myeloid cells in PC was greatly reduced in response to ONX 0914. Thus, immunoproteasome inhibition shows remarkable efficacy against PC progression in vivo and impedes tumor recurrence in CRPC-TRAMP mice by blocking the immunosuppressive inflammatory response in the tumor microenvironment. In conclusion, we show that the immunoproteasome is a promising drug target for the treatment of PC.

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ISO 690KÖRNER, Julia, Dennis HORVATH, Franziska OLIVERI, Jun LI, Michael BASLER, 2023. Suppression of prostate cancer and amelioration of the immunosuppressive tumor microenvironment through selective immunoproteasome inhibition. In: OncoImmunology. Taylor & Francis. 2023, 12(1), 2156091. ISSN 2162-4011. eISSN 2162-402X. Available under: doi: 10.1080/2162402X.2022.2156091
BibTex
@article{Korner2023Suppr-59641,
  year={2023},
  doi={10.1080/2162402X.2022.2156091},
  title={Suppression of prostate cancer and amelioration of the immunosuppressive tumor microenvironment through selective immunoproteasome inhibition},
  number={1},
  volume={12},
  issn={2162-4011},
  journal={OncoImmunology},
  author={Körner, Julia and Horvath, Dennis and Oliveri, Franziska and Li, Jun and Basler, Michael},
  note={Article Number: 2156091}
}
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