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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

Hellsten, Rebecka LU ; Lilljebjörn, Lisa; Johansson, Martin; Leandersson, Karin LU and Bjartell, Anders LU (2019) In Prostate 79(14). p.1611-1621
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... (More)

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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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cancer therapy, castration-resistant prostate cancer, myeloid-derived suppressor cells, signal transducer and activator of transcription 3, STAT3 inhibitor
in
Prostate
volume
79
issue
14
pages
11 pages
publisher
John Wiley & Sons
external identifiers
  • scopus:85071509939
ISSN
0270-4137
DOI
10.1002/pros.23885
language
English
LU publication?
yes
id
a6efee06-faae-4dc0-baf6-7320d45a73e7
date added to LUP
2019-09-23 12:49:13
date last changed
2019-11-05 05:26:25
@article{a6efee06-faae-4dc0-baf6-7320d45a73e7,
  abstract     = {<p>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<sup>+</sup> HLA-DR<sup>−/lo</sup>). 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.</p>},
  author       = {Hellsten, Rebecka and Lilljebjörn, Lisa and Johansson, Martin and Leandersson, Karin and Bjartell, Anders},
  issn         = {0270-4137},
  keyword      = {cancer therapy,castration-resistant prostate cancer,myeloid-derived suppressor cells,signal transducer and activator of transcription 3,STAT3 inhibitor},
  language     = {eng},
  number       = {14},
  pages        = {1611--1621},
  publisher    = {John Wiley & Sons},
  series       = {Prostate},
  title        = {The STAT3 inhibitor galiellalactone inhibits the generation of MDSC-like monocytes by prostate cancer cells and decreases immunosuppressive and tumorigenic factors},
  url          = {http://dx.doi.org/10.1002/pros.23885},
  volume       = {79},
  year         = {2019},
}