Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan; Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei, Taiwan.
Cancer Lett. 2024 Aug 28;598:217090. doi: 10.1016/j.canlet.2024.217090. Epub 2024 Jun 28.
The tumor microenvironment (TME) of prostate cancer (PCa) is characterized by high levels of immunosuppressive molecules, including cytokines and chemokines. This creates a hostile immune landscape that impedes effective immune responses. The interleukin-1 (IL-1) receptor antagonist (IL1RN), a key anti-inflammatory molecule, plays a significant role in suppressing IL-1-related immune and inflammatory responses. Our research investigates the oncogenic role of IL1RN in PCa, particularly its interactions with muscarinic acetylcholine receptor 4 (CHRM4), and its involvement in driving immunosuppressive pathways and M2-like macrophage polarization within the PCa TME. We demonstrate that following androgen deprivation therapy (ADT), the IL1RN-CHRM4 interaction in PCa activates the MAPK/AKT signaling pathway. This activation upregulates the transcription factors E2F1 and MYCN, stimulating IL1RN production and creating a positive feedback loop that increases CHRM4 abundance in both PCa cells and M2-like macrophages. This ADT-driven IL1RN/CHRM4 axis significantly enhances immune checkpoint markers associated with neuroendocrine differentiation and treatment-resistant outcomes. Higher serum IL1RN levels are associated with increased disease aggressiveness and M2-like macrophage markers in advanced PCa patients. Additionally, elevated IL1RN levels correlate with better clinical outcomes following immunotherapy. Clinical correlations between IL1RN and CHRM4 expression in advanced PCa patients and neuroendocrine PCa organoid models highlight their potential as therapeutic targets. Our data suggest that targeting the IL1RN/CHRM4 signaling could be a promising strategy for managing PCa progression and enhancing treatment responses.
前列腺癌（PCa）的肿瘤微环境（TME）以高水平的免疫抑制分子为特征，包括细胞因子和趋化因子。这就形成了一个不利于有效免疫反应的免疫抑制性景观。白细胞介素-1（IL-1）受体拮抗剂（IL1RN）作为一种关键的抗炎分子，在抑制与 IL-1 相关的免疫和炎症反应方面发挥着重要作用。我们的研究调查了 IL1RN 在 PCa 中的致癌作用，特别是它与毒蕈碱乙酰胆碱受体 4（CHRM4）的相互作用，以及它在驱动免疫抑制途径和 PCa TME 中的 M2 样巨噬细胞极化中的作用。我们证明，在去势治疗（ADT）后，PCa 中的 IL1RN-CHRM4 相互作用激活了 MAPK/AKT 信号通路。这种激活上调了转录因子 E2F1 和 MYCN，刺激了 IL1RN 的产生，并形成了一个正反馈回路，增加了 PCa 细胞和 M2 样巨噬细胞中 CHRM4 的丰度。这种 ADT 驱动的 IL1RN/CHRM4 轴显著增强了与神经内分泌分化和治疗抵抗相关的免疫检查点标志物。在晚期 PCa 患者中，较高的血清 IL1RN 水平与疾病侵袭性增加和 M2 样巨噬细胞标志物增加相关。此外，IL1RN 水平升高与免疫治疗后更好的临床结果相关。在晚期 PCa 患者和神经内分泌 PCa 类器官模型中，IL1RN 和 CHRM4 表达的临床相关性突出了它们作为治疗靶点的潜力。我们的数据表明，靶向 IL1RN/CHRM4 信号可能是管理 PCa 进展和增强治疗反应的一种有前途的策略。
