Abstract 112: Tumor-associated macrophages promote enzalutamide resistance in microscale castrate-resistant prostate cancer models

Abstract

Abstract Background: Despite recent advances in hormonal therapy for men with advanced prostate cancer, the development of therapeutic resistance continues to limit the efficacy of hormone-directed agents. This includes resistance to second-generation anti-androgens, such as enzalutamide, that can improve both morbidity and overall survival in men with castrate-resistant prostate cancer (CRPC). Tumor-associated macrophages (TAMs) are myeloid immune cells within the tumor microenvironment (TME), which have been shown to promote resistance to hormone therapies in prostate cancer. While they are known to have a role in the development of castrate resistance, their role in enzalutamide resistance is not yet understood. Methods: We have developed a novel microscale cell culture platform that enables efficient multi-culture of >5 primary cell populations along with multiplexed analysis of cell viability, migration, mRNA and protein expression, and secretion of secretory factors. Utilizing this platform, we cultured androgen-sensitive prostate cancer cells (LNCaPs) with primary monocyte-derived macrophages (MDMs) as well as additional primary stromal and immune cell populations (T cells, fibroblasts). Cultures were treated with enzalutamide therapy and analyzed for cell viability, mRNA and protein expression, and cytokine secretion. Results: After enzalutamide treatment, LNCaPs in co-culture with primary MDMs had an increase in viable cell number compared to LNCaPs in monoculture. CSF-1 expression was elevated in LNCaPs cultured with MDMs, and this expression was increased even further with enzalutamide treatment. In MDMs cultured with LNCaPs, there was a significant increase in expression of the CSF-1-responsive genes IL-10 and CCL18. This effect was observed consistently in MDMs from multiple patients. Conclusions: Within microscale tumor models, we have demonstrated that primary, patient-derived MDMs promote resistance to enzalutamide therapy in androgen-sensitive prostate cancer cells. An increase in CSF-1 expression by LNCaPs in our tumor models was associated with an increase in CSF-1 responsive genes within the MDMs, including IL-10 and CCL18. Elevated expression of both of these cytokines has been associated with more aggressive prostate cancers in patients. IL-10 and CCL18 have also been shown to protect against apoptosis in vitro as well as promote immune suppression in vivo. Our findings suggest that CSF-1 secretion by tumor cells may promote hormone resistance in prostate cancer through TAM-mediated secretion of IL-10 and CCL18. These pathways represent potentially high-value targets to limit or prevent the development of castrate resistance in men with advanced prostate cancer. Further studies targeting the secretion of CSF-1, IL-10, and CCL18 in combination with enzalutamide treatment are ongoing. Citation Format: David Kosoff, Jiaquan Yu, Vikram Suresh, David J. Beebe, Joshua M. Lang. Tumor-associated macrophages promote enzalutamide resistance in microscale castrate-resistant prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 112.