IL-23 secreted by myeloid cells drives castration-resistant prostate cancer

Calcinotto, Arianna; Spataro, Clarissa; Zagato, Elena; Mitri, Diletta Di; Gil, Veronica; Crespo, Mateus; Bernardis, Gaston De; Losa, Marco; Mirenda, Michela; Pasquini, Emiliano; Rinaldi, Andrea; Sumanasuriya, Semini; Lambros, Maryou; Neeb, Antje; Lucianò, Roberta; Bravi, Carlo Andrea; Nava-Rodrigues, Daniel; Dolling, David; Prayer-Galetti, Tommaso; Ferreira, Ana; Briganti, Alberto; Esposito, Antonio; Barry, Simon T.; Yuan, Wei; Sharp, Adam; Bono, Johann S. de; Alimonti, Andrea

doi:10.1038/s41586-018-0266-0

Cited by 293 publications

(326 citation statements)

References 45 publications

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“…Finally, immunofluorescence and flow cytometry analyses revealed that, in patients with castration-resistant prostate cancer (CRPC), tumor-infiltrating myeloid-derived suppressor cells with the neutrophil phenotype (CD11b + CD33 + CD15 + cells, polymorphonuclear cell-myeloid-derived suppressor cells) express IL-23. 56 In summary, we show that highly pure neutrophils express IL-23, which is capable…”

Section: Discussionmentioning

confidence: 68%

“…However, in these experiments the infected neutrophils were also reported to express IL‐17, which, according to our previous work, does not occur. Finally, immunofluorescence and flow cytometry analyses revealed that, in patients with castration‐resistant prostate cancer (CRPC), tumor‐infiltrating myeloid‐derived suppressor cells with the neutrophil phenotype (CD11b + CD33 + CD15 + cells, polymorphonuclear cell‐myeloid‐derived suppressor cells) express IL‐23 …”

Section: Discussionmentioning

confidence: 99%

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Human neutrophils activated via TLR8 promote Th17 polarization through IL-23

Tamassia

Arruda‐Silva

Wright

et al. 2019

Journal of Leukocyte Biology

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Human neutrophils contribute to the regulation of inflammation via the generation of a range of cytokines that affect all elements of the immune system. Here, we investigated their ability to express some of the members of the IL‐12 family after incubation with TLR8 agonists. Highly pure human neutrophils were thus incubated for up to 48 h with or without R848, or other TLR8 agonists, to then measure the expression levels of transcripts and proteins for IL‐12 family member subunits by RNA‐seq, reverse transcription quantitative PCR, and ELISA. We show a TLR8‐mediated inducible expression of IL‐12B and IL‐23A, but not IL‐12A, mRNA, which occurs via chromatin remodeling (as assessed by ChIP‐seq), and subsequent production of IL‐23 and IL‐12B, but no IL‐12, proteins. Induction of IL‐23 requires endogenous TNF‐α, as both mRNA and protein levels were blocked in TLR8‐activated neutrophils via a TNF‐α‐neutralizing Ab. We also show that supernatants from TLR8‐activated neutrophils, but not autologous monocytes, induce the differentiation of Th17 cells from naïve T cells in an IL‐23‐dependent fashion. This study unequivocally demonstrates that highly pure human neutrophils express and produce IL‐23, further supporting the key roles played by these cells in the important IL‐17/IL‐23 network and Th17 responses.

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Section: Discussionmentioning

confidence: 68%

Section: Discussionmentioning

confidence: 99%

Human neutrophils activated via TLR8 promote Th17 polarization through IL-23

Tamassia

Arruda‐Silva

Wright

et al. 2019

Journal of Leukocyte Biology

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“…Arginase‐1 expression and activity in monocytes and MDSCs varies considerably between individuals, which may explain why we did not find a consistent effect on arginase‐1 expression in this study. IL23 secreted by granulocytic MDSCs is observed to be involved in CRPC . However, in this study, we focus on monocytic MDSCs and we did not observe a significant increase in IL23 expression in the monocytic MDSCs generated by prostate cancer cell CM.…”

Section: Discussionmentioning

confidence: 65%

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

et al. 2019

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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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“…High numbers of MDSCs in a Pten -/setting provide a protective effect on PCa cells from senescence, therefore sustaining tumour growth 26 , 27 . Mechanistically this has been observed to occur in CRPC patients and in transgenic prostate cancer models through the activation of the AR signalling due to paracrine IL-23 secretion by MDSCs 28 . Furthermore, influx of tumour MDSCs has been detected following RT, an observation which has been previously associated with the RT-induced up-regulation of STING expression in tumour cells 19 , 29 , 30 .…”

Section: Discussionmentioning

confidence: 98%

Development of a novel allograft model of prostate cancer: a new tool to inform clinical translation

Haughey

Mukherjee

Steele

et al. 2020

Preprint

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Background:Allograft models enable characterisation of genomic drivers and treatment responses by modelling immune and micro-environmental changes more accurately than xenografts. Despite this, few models are available to the prostate cancer (PCa) community. This study presents a novel allograft model of high-risk, localised PCa. In characterising this model we have focused on its response to radiotherapy (RT). Methods:The DVL3 cell line was derived from a transgenic trp53 -/-/Pten -/mouse model and characterised both in vitro and in vivo. The DVL3 cells were allografted and response to RT was investigated and compared to the TRAMP-C1 model. Extensive tumour profiling in the DVL3 model was performed using flow cytometry, immunohistochemistry and RNA-seq. Results:In vitro the DVL3 cells expressed basal and luminal markers. DVL3 cells formed tumours with distinct glandular morphology which expressed androgen receptor, similar to human localised PC. DVL3 tumour growth was delayed following administration of fractionated RT, with infiltration of myeloid derived suppressor cells (MDSC). Conclusions:The DVL3 allograft model represents substantial progress in PCa modelling, displaying; luminal differentiation, strong AR expression, and an immunosuppressive microenvironment, similar to observations in high-risk PCa patients. This model is ideally suited for development and validation of novel therapeutics, in particular immune-modulatory agents in combination with RT.

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IL-23 secreted by myeloid cells drives castration-resistant prostate cancer

Cited by 293 publications

References 45 publications

Human neutrophils activated via TLR8 promote Th17 polarization through IL-23

Human neutrophils activated via TLR8 promote Th17 polarization through IL-23

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

Development of a novel allograft model of prostate cancer: a new tool to inform clinical translation

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