雄性激素剝奪誘導第一型介白素受體拮抗劑正調控促進攝護腺癌之免疫抑制及神經內分泌分化

游家豪¹、溫玉清^1,2、陳威宇³、劉晏年⁴

¹臺北市立萬芳醫院泌尿科－委託臺北醫學大學辦理

²臺北醫學大學泌尿學科

³臺北市立萬芳醫院病理科－委託臺北醫學大學辦理

⁴臺北醫學大學癌症生物學與藥物研發研究所

Androgen deprivation-induced interleukin 1 receptor antagonist upregulation promotes immunosuppression and neuroendocrine differentiation in prostate cancer

Chia-Hao You¹, Yu-Ching Wen^1,2, Wei-Yu Chen³, Yen-Nien Liu⁴

¹ Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

² Department of Urology, School of Medicine, College of Medicine, Taipei MedicalUniversity, Taipei, Taiwan

³ Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan

⁴ Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

Purpose:

Androgen deprivation therapy (ADT) is a key treatment for prostate cancer (PCa), but resistance often leads to the development of neuroendocrine prostate cancer (NEPC), a more aggressive form.This study aims to investigate the role of cholinergic receptor muscarinic 4 (CHRM4) and its contribution to the upregulation of interleukin 1 receptor antagonist (IL1RN), and how these molecules influence immunosuppression and neuroendocrine differentiation (NED) in ADT-resistant PCa.

Material and Methods:

Using AR-positive C4-2 cells engineered to overexpress CHRM4, we observed significant increases in IL1RN levels. This finding was confirmed through cytokine array analysis, gene expression profiling, and clinical dataset evaluation.

Functional Analysis: Cell proliferation, migration and tumor growth under the effect of CHRM4 inhibition were evaluated using functional assays. Kaplan-Meier survival analyses from the GSE21032 dataset, which included 28 normal prostate samples, 98 primary PCa samples, and 13 metastatic PCa samples, were performed to assess patient survival outcomes.

Result:

Significant increases in IL1RN levels were observed in CHRM4-overexpressing cells. Increased CHRM4 and IL1RN expression were linked to enzalutamide resistance, NEPC progression, and increased expression of neuroendocrine (CHGA, SYP, ENO2) and stem cell markers (NANOG, SOX2). IL1RN overexpression promoted cell proliferation, migration, and tumor growth, while CHRM4 inhibition reduced these effects which suggesting that the IL1RN/CHRM4 axis promoting malignancy.

Kaplan-Meier analysis showed a strong correlation between high IL1RN levels and poor patient survival outcomes. In vivo experiments confirmed that targeting CHRM4 with ceritinib attenuated IL1RN-driven tumor growth and sphere formation.

Conclusion:

IL1RN, upregulated by CHRM4 under ADT, plays a key role in promoting an immunosuppressive tumor microenvironment and NED in PCa.

Targeting the IL1RN/CHRM4 axis presents a potential therapeutic strategy for treating ADT-resistant PCa and NEPC, as confirmed by in vivo experiments with ceritinib attenuated tumor growth and sphere formation.