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

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.

Human Isogenic Cell Line Models for Neutrophils and Myeloid-Derived Suppressor Cells

“…As stated above, STAT3 is critical for the activation of immunosuppressive myeloid cells including MDSCs [ 42 ]. STAT3 inhibitors or STAT3-targeted oligonucleotide agents reduce the number and abolish the immunosuppressive activity of MDSCs in mouse models and cancer patients [ 30 , 43 , 44 , 45 ]. We tested the effect of ATRA and a STAT3 inhibitor BP-1-102 [ 46 ] on iMDSC differentiation from HL60 by including these two agents in the condition A (DMSO + GM-CSF + IL6) of HL60 differentiation.…”

PIM kinase inhibition: co-targeted therapeutic approaches in prostate cancer

“…92,93 The STAT3-targeted inhibitor galiellalactone has been shown to be successful in preventing the generation of MDSCs and thus suppressing the immune response against PCa cells. 87 Inhibition of PIM by M-110 and SGI-1776 can indirectly decrease levels of phosphorylated STAT3, but not STAT5, in cell models, which contributed to downregulation of PIM3 (ref. 94 ).…”

Modeling of the immune response in the pathogenesis of solid tumors and its prognostic significance

“…The use of STAT3 inhibitors in prostate cancer limited tumor-associated MDSCs and inhibited interleukin-1β (IL-1β), IL-10 and IL-6 synthesis by monocyte cultures [95]. STAT3 inhibition in liver-associated MDSCs (L-MDSCs) has been found to exhibit antitumor activity, whereas a decreased level of STAT3 phosphorylation also reduced the size of the L-MDSC population, which in turn led to an increased anticancer activity of chimeric antigen receptor T cells (CAR-T) [96].…”