IL‐1β Is an Androgen‐Responsive Target in Macrophages for Immunotherapy of Prostate Cancer

Great attention is paid to the role of androgen receptor (AR) as a central transcriptional factor in driving the growth of prostate cancer (PCa) epithelial cells. However, the understanding of the role of androgen in PCa‐infiltrated immune cells and the impact of androgen deprivation therapy (ADT),...

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Published in:	Advanced science 2023-06, Vol.10 (17), p.e2206889-n/a
Main Authors:	Wang, Deng, Cheng, Chaping, Chen, Xinyu, Wang, Jinming, Liu, Kaiyuan, Jing, Na, Xu, Penghui, Xi, Xialian, Sun, Yujiao, Ji, Zhongzhong, Zhao, Huifang, He, Yuman, Zhang, Kai, Du, Xinxing, Dong, Baijun, Fang, Yuxiang, Zhang, Pengcheng, Qian, Xueming, Xue, Wei, Gao, Wei‐Qiang, Zhu, Helen He
Format:	Article
Language:	eng
Subjects:	Androgen Antagonists androgen deprivation therapy androgen receptor Androgens Animals Breast cancer Cytokines Cytotoxicity Flow cytometry Gene expression Humans IL‐1β immune therapy Immunotherapy Lymphocytes Macrophages - metabolism Male Melanoma Mice Prostate cancer Prostatic Neoplasms - immunology Prostatic Neoplasms - therapy Statistical analysis Tumor Microenvironment Tumors tumor‐associated macrophage
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Summary:	Great attention is paid to the role of androgen receptor (AR) as a central transcriptional factor in driving the growth of prostate cancer (PCa) epithelial cells. However, the understanding of the role of androgen in PCa‐infiltrated immune cells and the impact of androgen deprivation therapy (ADT), the first‐line treatment for advanced PCa, on the PCa immune microenvironment remains limited. On the other hand, immune checkpoint blockade has revolutionized the treatment of certain cancer types, but fails to achieve any benefit in advanced PCa, due to an immune suppressive environment. In this study, it is reported that AR signaling pathway is evidently activated in tumor‐associated macrophages (TAMs) of PCa both in mice and humans. AR acts as a transcriptional repressor for IL1B in TAMs. ADT releases the restraint of AR on IL1B and therefore leads to an excessive expression and secretion of IL‐1β in TAMs. IL‐1β induces myeloid‐derived suppressor cells (MDSCs) accumulation that inhibits the activation of cytotoxic T cells, leading to the immune suppressive microenvironment. Critically, anti‐IL‐1β antibody coupled with ADT and the immune checkpoint inhibitor anti‐PD‐1 antibody exerts a stronger anticancer effect on PCa following castration. Together, IL‐1β is an important androgen‐responsive immunotherapeutic target for advanced PCa. Androgen receptor signaling is active in tumor‐associated macrophages (TAMs) and inhibits the transcription of IL‐1β in prostate cancer. Androgen deprivation therapy (ADT) promotes the production of IL‐1β by TAMs, leading to enhanced myeloid‐derived suppressor cells recruitment and immune therapy resistance. Targeting IL‐1β and blocking immune checkpoints in combination with ADT could be a promising therapeutic approach for advanced prostate cancer.
ISSN:	2198-3844 2198-3844