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

ABSTRACT

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.

KEYWORDS:

• Prostate cancer
• immunoproteasome
• LMP7
• myeloid-derived suppressor cells (MDSC)
• castration-resistant prostate cancer (CRPC)
• TRAMP
• ONX 0914

Acknowledgments

We gratefully acknowledge deceased Prof. Dr. Marcus Groettrup who supervised the whole project and acquired funding resources. We are thankful to Christopher J. Kirk for the generous contribution of ONX 0914. We thank the personnel of the Animal Research Facility of Konstanz University for professional animal care taking. Flow cytometric analyses were performed in the flow cytometry center of the University of Konstanz, FlowKon.

Author contributions

JK, DH, and JL designed and performed experiments and evaluated data. JK wrote the manuscript. FO and MB provided experimental help and technical advice with mouse work and histology and corrected the manuscript. MB corrected and refined the manuscript.

Disclosure statement

The authors report there are no competing interests to declare.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2022.2156091

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This study was supported by the German Research Foundation (DFG) grant GR1517-27-1 to MB and the National Natural Science Foundation of China (grant Nr. 81870304) to JL.