Effective treatment of advanced prostate cancer persists as a significant clinical need as only 30% of patients with distant disease survive to 5 years after diagnosis. Targeting signaling and tumor cell–immune cell interactions in the tumor microenvironment has led to the development of powerful immunotherapeutic agents, however, the prostate tumor milieu remains impermeable to these strategies highlighting the need for novel therapeutic targets. In this study, we provide compelling evidence to support the role of the RON receptor tyrosine kinase as a major regulator of macrophages in the prostate tumor microenvironment. We show that loss of RON selectively in prostate epithelial cells leads to significantly reduced prostate tumor growth and metastasis and is associated with increased intratumor infiltration of macrophages. We further demonstrate that prostate epithelial RON loss induces transcriptional reprogramming of macrophages to support expression of classical M1 markers and suppress expression of alternative M2 markers. Interestingly, our results show epithelial RON activation drives upregulation of RON expression in macrophages as a positive feed-forward mechanism to support prostate tumor growth. Using 3D coculture assays, we provide additional evidence that epithelial RON expression coordinates interactions between prostate tumor cells and macrophages to promote macrophage-mediated tumor cell growth. Taken together, our results suggest that RON receptor signaling in prostate tumor cells directs the functions of macrophages in the prostate tumor microenvironment to promote prostate cancer. Implications: Epithelial RON is a novel immunotherapeutic target that is responsible for directing the macrophage antitumor immune response to support prostate tumor growth and progression.

中文翻译：

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前列腺上皮 RON 信号促进 M2 巨噬细胞激活以驱动前列腺肿瘤生长和进展

晚期前列腺癌的有效治疗仍然是重要的临床需求，因为只有 30% 的远处疾病患者在诊断后存活 5 年。肿瘤微环境中的靶向信号传导和肿瘤细胞-免疫细胞相互作用导致了强大的免疫治疗剂的开发，然而，前列腺肿瘤环境仍然无法渗透这些策略，这突出了对新治疗靶点的需求。在这项研究中，我们提供了令人信服的证据来支持 RON 受体酪氨酸激酶作为前列腺肿瘤微环境中巨噬细胞的主要调节剂的作用。我们表明，在前列腺上皮细胞中选择性地丢失 RON 会导致前列腺肿瘤的生长和转移显着减少，并且与巨噬细胞的肿瘤内浸润增加有关。我们进一步证明前列腺上皮 RON 损失诱导巨噬细胞的转录重编程以支持经典 M1 标志物的表达并抑制替代 M2 标志物的表达。有趣的是，我们的结果显示上皮 RON 激活驱动巨噬细胞中 RON 表达的上调，作为支持前列腺肿瘤生长的正前馈机制。使用 3D 共培养分析，我们提供了额外的证据，表明上皮 RON 表达协调前列腺肿瘤细胞和巨噬细胞之间的相互作用，以促进巨噬细胞介导的肿瘤细胞生长。总之，我们的结果表明前列腺肿瘤细胞中的 RON 受体信号传导指导前列腺肿瘤微环境中巨噬细胞的功能以促进前列腺癌。含义：