Division of Urological Cancers, Department of Translational Medicine, Lund University, Malmö, Sweden.
Glactone Pharma AB, Helsingborg, Sweden.
Prostate. 2019 Oct;79(14):1611-1621. doi: 10.1002/pros.23885. Epub 2019 Jul 26.
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.
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 ). The secretion and gene expression of immunosuppressive factors and inflammatory cytokines from prostate cancer cells and monocytes were investigated.
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.
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.
转录因子信号转导子和转录激活子 3（STAT3）参与癌症药物耐药性、转移和免疫抑制，已被确定为新型抗癌药物的有前途的治疗靶点。髓源抑制细胞（MDSC）在抑制抗肿瘤免疫中起主要作用，STAT3 参与 MDSC 的积累、产生和功能。因此，靶向 STAT3 有可能逆转癌症中的免疫抑制。本研究旨在研究小分子 STAT3 抑制剂岩藻依聚糖对前列腺癌细胞诱导单核细胞产生 MDSC 的影响，以及对免疫抑制因子和炎症细胞因子的影响。
原代人单核细胞与前列腺癌细胞（DU145、PC3 和 LNCaP-IL6）或前列腺癌细胞条件培养基（CM）共培养，存在或不存在 STAT3 抑制剂岩藻依聚糖。通过流式细胞术分析单核细胞的 MDSC 样表型（CD14 HLA-DR ）。研究了前列腺癌细胞和单核细胞中免疫抑制因子和炎症细胞因子的分泌和基因表达。
岩藻依聚糖阻断了前列腺癌细胞诱导的具有免疫抑制表型的 MDSC 样单核细胞的产生。与前列腺癌细胞 CM 共培养的单核细胞显示磷酸化 STAT3 表达增加。前列腺癌细胞增加了单核细胞中白细胞介素 1β（IL1β）、IL10 和 IL6 的表达，岩藻依聚糖抑制了这一表达。此外，岩藻依聚糖降低了单核细胞中吲哚胺 2,3-双加氧酶基因的表达。岩藻依聚糖本身降低了前列腺癌细胞中白细胞介素 8 和粒细胞巨噬细胞集落刺激因子的水平。
STAT3 抑制剂岩藻依聚糖可能防止前列腺癌细胞诱导的 MDSC 产生，并逆转前列腺癌细胞与 MDSC 相互作用引起的免疫抑制机制。这是治疗前列腺癌的一种潜在新免疫治疗方法。
