IL-1β Is an Androgen-Responsive Target in Macrophages for Immunotherapy of Prostate Cancer.
IL-1β Is an Androgen-Responsive Target in Macrophages for Immunotherapy of Prostate Cancer.
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DOI：
10.1002/advs.202206889
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发表时间：
2023-06
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雄激素受体（AR）作为一个中心转录因子在前列腺癌（PCa）上皮细胞生长中的作用备受关注。然而，雄激素在前列腺癌浸润免疫细胞中的作用以及雄激素剥夺疗法（ADT）（晚期前列腺癌的一线治疗）对前列腺癌免疫微环境的影响的理解仍然有限。另一方面，免疫检查点阻断已经彻底改变了某些癌症类型的治疗，但由于免疫抑制环境，未能在晚期PCa中取得任何益处。本研究报道，小鼠和人的前列腺癌肿瘤相关巨噬细胞（tumor - associated macrophages, tam）均明显激活AR信号通路。AR在tam中作为IL1B的转录抑制因子。ADT释放AR对IL - 1b的抑制，从而导致tam中IL - 1β的过度表达和分泌。IL - 1β诱导髓源性抑制细胞（MDSCs）积累，抑制细胞毒性T细胞的激活，导致免疫抑制微环境。关键是，抗IL - 1β抗体联合ADT和免疫检查点抑制剂抗PD - 1抗体对去势后的PCa具有更强的抗癌作用。总之，IL - 1β是晚期前列腺癌重要的雄激素应答性免疫治疗靶点。雄激素受体信号在肿瘤相关巨噬细胞（tam）中活跃，并抑制前列腺癌中IL - 1β的转录。雄激素剥夺疗法（ADT）通过tam促进IL - 1β的产生，导致髓源性抑制细胞募集增强和免疫治疗抵抗。靶向IL - 1β和阻断免疫检查点联合ADT可能是一种很有前途的晚期前列腺癌治疗方法。
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.
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影响因子：
8
作者：
Kaler, P.;Augenlicht, L.;Klampfer, L.
通讯作者：
Klampfer, L.
Interleukin-1家族：回到未来。
影响因子：
32.4
作者：
Garlanda C;Dinarello CA;Mantovani A
通讯作者：
Mantovani A
影响因子：
8.7
作者：
Dinarello CA
通讯作者：
Dinarello CA
DOI：
10.1158/1078-0432.ccr-12-3327
发表时间：
2013-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Gucalp A;Tolaney S;Isakoff SJ;Ingle JN;Liu MC;Carey LA;Blackwell K;Rugo H;Nabell L;Forero A;Stearns V;Doane AS;Danso M;Moynahan ME;Momen LF;Gonzalez JM;Akhtar A;Giri DD;Patil S;Feigin KN;Hudis CA;Traina TA;Translational Breast Cancer Research Consortium (TBCRC 011)
通讯作者：
Translational Breast Cancer Research Consortium (TBCRC 011)
影响因子：
82.9
作者：
Bezzi, Marco;Seitzer, Nina;Pandolfi, Pier Paolo
通讯作者：
Pandolfi, Pier Paolo