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      The STAT3 inhibitor galiellalactone inhibits the generation of MDSC‐like monocytes by prostate cancer cells and decreases immunosuppressive and tumorigenic factors

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          Abstract

          Background

          The transcription factor signal transducer and activator of transcription 3 (STAT3) is implicated in cancer drug resistance, metastasis, and immunosuppression and has been identified as a promising therapeutic target for new anticancer drugs. Myeloid‐derived suppressor cells (MDSCs) play a major role in the suppression of antitumor immunity and STAT3 is involved in the accumulation, generation, and function of MDSCs. Thus, targeting STAT3 holds the potential of reversing immunosuppression in cancer. This study aims to investigate the effect of the small molecule STAT3 inhibitor galiellalactone on prostate cancer cell– induced generation of MDSCs from monocytes and the effect on immunosuppressive factors and inflammatory cytokines.

          Methods

          Primary human monocytes were cocultured with prostate cancer cells (DU145, PC3, and LNCaP‐IL6) or with conditioned medium (CM) from prostate cancer cells in the presence or absence of the STAT3 inhibitor galiellalactone. Monocytes were analyzed by flow cytometry for an MDSC‐like phenotype (CD14 + HLA‐DR −/lo). The secretion and gene expression of immunosuppressive factors and inflammatory cytokines from prostate cancer cells and monocytes were investigated.

          Results

          Galiellalactone blocked the prostate cancer cell–induced generation of MDSC‐like monocytes with an immunosuppressive phenotype ex vivo. Monocytes cultured with CM from prostate cancer cells showed increased expression of phosphorylated STAT3. Prostate cancer cells increased the expression of interleukin1β (IL1β), IL10, and IL6 in monocytes which was inhibited by galiellalactone. In addition, galiellalactone decreased indoleamine 2,3‐dioxygenase gene expression in monocytes. Galiellalactone reduced the levels of IL8 and granulocyte macrophage‐colony stimulating factor in prostate cancer cells per se.

          Conclusion

          The STAT3 inhibitor galiellalactone may prevent the prostate cancer cell–induced generation of MDSCs and reverse the immunosuppressive mechanisms caused by the interplay between prostate cancer cells and MDSCs. This is a potential new immunotherapeutic approach for the treatment of prostate cancer.

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          Most cited references34

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          Myeloid-Derived Suppressor Cells: Critical Cells Driving Immune Suppression in the Tumor Microenvironment.

          Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells that suppress innate and adaptive immunity. MDSCs are present in many disease settings; however, in cancer, they are a major obstacle for both natural antitumor immunity and immunotherapy. Tumor and host cells in the tumor microenvironment (TME) produce a myriad of pro-inflammatory mediators that activate MDSCs and drive their accumulation and suppressive activity. MDSCs utilize a variety of mechanisms to suppress T cell activation, induce other immune-suppressive cell populations, regulate inflammation in the TME, and promote the switching of the immune system to one that tolerates and enhances tumor growth. Because MDSCs are present in most cancer patients and are potent immune-suppressive cells, MDSCs have been the focus of intense research in recent years. This review describes the history and identification of MDSCs, the role of inflammation and intracellular signaling events governing MDSC accumulation and suppressive activity, immune-suppressive mechanisms utilized by MDSCs, and recent therapeutics that target MDSCs to enhance antitumor immunity.
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            Update on Systemic Prostate Cancer Therapies: Management of Metastatic Castration-resistant Prostate Cancer in the Era of Precision Oncology

            Introduction of novel agents for the management of advanced prostate cancer provides a range of treatment options with notable benefits for men with metastatic castration-resistant prostate cancer (mCRPC). At the same time, understanding of optimal patient selection, effective sequential use, and development of resistance patterns remains incomplete.
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              Interleukin-1 Beta—A Friend or Foe in Malignancies?

              Interleukin-1 beta (IL-1β) is induced by inflammatory signals in a broad number of immune cell types. IL-1β (and IL-18) are the only cytokines which are processed by caspase-1 after inflammasome-mediated activation. This review aims to summarize current knowledge about parameters of regulation of IL-1β expression and its multi-facetted role in pathophysiological conditions. IL-1 signaling activates innate immune cells including antigen presenting cells, and drives polarization of CD4+ T cells towards T helper type (Th) 1 and Th17 cells. Therefore, IL-1β has been attributed a largely beneficial role in resolving acute inflammations, and by initiating adaptive anti-tumor responses. However, IL-1β generated in the course of chronic inflammation supports tumor development. Furthermore, IL-1β generated within the tumor microenvironment predominantly by tumor-infiltrating macrophages promotes tumor growth and metastasis via different mechanisms. These include the expression of IL-1 targets which promote neoangiogenesis and of soluble mediators in cancer-associated fibroblasts that evoke antiapoptotic signaling in tumor cells. Moreover, IL-1 promotes the propagation of myeloid-derived suppressor cells. Using genetic mouse models as well as agents for pharmacological inhibition of IL-1 signaling therapeutically applied for treatment of IL-1 associated autoimmune diseases indicate that IL-1β is a driver of tumor induction and development.
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                Author and article information

                Contributors
                rebecka.hellsten@med.lu.se
                Journal
                Prostate
                Prostate
                10.1002/(ISSN)1097-0045
                PROS
                The Prostate
                John Wiley and Sons Inc. (Hoboken )
                0270-4137
                1097-0045
                26 July 2019
                01 October 2019
                : 79
                : 14 ( doiID: 10.1002/pros.v79.14 )
                : 1611-1621
                Affiliations
                [ 1 ] Division of Urological Cancers, Department of Translational Medicine Lund University Malmö Sweden
                [ 2 ] Glactone Pharma AB Helsingborg Sweden
                [ 3 ] Cancer Immunology, Department of Translational Medicine Lund University Malmö Sweden
                Author notes
                [*] [* ] Correspondence Rebecka Hellsten, Associate professor, Center for Molecular Pathology, Jan Waldenströms gata 59, SUS Malmö, SE‐205 02 Malmö, Sweden.

                Email: rebecka.hellsten@ 123456med.lu.se

                Author information
                http://orcid.org/0000-0002-3735-5636
                Article
                PROS23885
                10.1002/pros.23885
                6771992
                31348843
                c8eb6454-9d9e-44b3-aba6-42f2a3cb9127
                © 2019 The Authors. The Prostate Published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                History
                : 08 February 2019
                : 02 July 2019
                Page count
                Figures: 5, Tables: 0, Pages: 11, Words: 6273
                Funding
                Funded by: The Swedish Cancer Society
                Award ID: Research Grant
                Funded by: The Swedish Research Council
                Award ID: Research Grant
                Funded by: The Cancer Foundation at Skåne University Hospital Malmö
                Award ID: Research Grant
                Funded by: The Swedish Prostate Cancer Foundation
                Award ID: Research Grant
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                pros23885
                October 1, 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.9 mode:remove_FC converted:01.10.2019

                Sexual medicine
                cancer therapy,castration‐resistant prostate cancer,myeloid‐derived suppressor cells,signal transducer and activator of transcription 3,stat3 inhibitor

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