Abstract PR09: Macrophage promotion of anti-androgen resistance in prostate cancer bone disease

Metastatic castration resistant prostate cancer (mCRPC) is the final stage of prostate cancer (PC) that acquires resistance to androgen deprivation therapies (ADT). Despite many recent progresses in the mechanistic understanding of ADT resistance, the specific contribution of the metastatic microenvironment in mCRPC remains largely unknown. A novel in vivo model of androgen dependent bone metastatic PC was developed in address this question. Our identified that macrophages are the major stromal cells in bone metastatic PC. Using multiple genetic models, we demonstrated that macrophages, both monocyte-derived and bone resident populations, were critical for bone metastatic PC to develop resistance to enzalutamide, a clinically used anti-androgen. Mechanistically, macrophages drove resistance through induction of a wound healing like response in prostate cancer cells, which was strongly supported by bioinformatics analysis of multiple patient mCRPC datasets. Furthermore, macrophage depletion or SRC inhibition using a novel specific inhibitor significantly inhibited resistant growth of mCRPC. Together, our findings elucidated a novel mechanism of macrophage-induced anti-androgen resistance of metastatic PC and a promising therapeutic approach to treat this deadly disease. Citation Format: Xue-Feng Li, Cigdem Selli, Asier Unciti-Broceta, Neil O. Carragher, Hai-Yan Hu, Charles L. Sawyers, Bin-Zhi Qian. Macrophage promotion of anti-androgen resistance in prostate cancer bone disease [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr PR09.