Prostate stromal cells play a crucial role in the promotion of tumor growth and immune evasion in the tumor microenvironment (TME) through intricate molecular alterations in their interaction with prostate cancer (PCa) cells. While the impact of these cells on establishing an immunosuppressive response and influencing PCa aggressiveness remains incompletely understood. Our study shows that the activation of the leukemia inhibitory factor (LIF)/LIF receptor (LIFR) pathway in both prostate tumor and stromal cells, following androgen deprivation therapy (ADT), leads to the development of an immunosuppressive TME. Activation of LIF/LIFR signaling in PCa cells induces neuroendocrine differentiation (NED) and upregulates immune checkpoint expression. Inhibition of LIF/LIFR attenuates these effects, underscoring the crucial role of LIF/LIFR in linking NED to immunosuppression. Prostate stromal cells expressing LIFR contribute to NED and immunosuppressive marker abundance in PCa cells, while LIFR knockdown in prostate stromal cells reverses these effects. ADT‐driven LIF/LIFR signaling induces brain‐derived neurotrophic factor (BDNF) expression, which, in turn, promotes NED, aggressiveness, and immune evasion in PCa cells. Clinical analyses demonstrate elevated BDNF levels in metastatic castration‐resistant PCa (CRPC) and a positive correlation with programmed death‐ligand 1 (PDL1) and immunosuppressive signatures. This study shows that the crosstalk between PCa cells and prostate stromal cells enhances LIF/LIFR signaling, contributing to an immunosuppressive TME and NED in PCa cells through the upregulation of BDNF.

中文翻译：

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BDNF 在治疗诱导的神经内分泌前列腺癌中的免疫抑制作用

前列腺基质细胞通过与前列腺癌（PCa）细胞相互作用的复杂分子改变，在促进肿瘤生长和肿瘤微环境（TME）中的免疫逃避中发挥着至关重要的作用。然而这些细胞对建立免疫抑制反应和影响 PCa 侵袭性的影响仍不完全清楚。我们的研究表明，雄激素剥夺疗法（ADT）后，前列腺肿瘤和基质细胞中白血病抑制因子（LIF）/LIF受体（LIFR）途径的激活导致免疫抑制性TME的发展。PCa 细胞中 LIF/LIFR 信号的激活可诱导神经内分泌分化 (NED) 并上调免疫检查点表达。LIF/LIFR 的抑制可减弱这些效应，强调了 LIF/LIFR 在 NED 与免疫抑制之间的联系中的关键作用。表达 LIFR 的前列腺基质细胞有助于 PCa 细胞中的 NED 和免疫抑制标记丰度，而前列腺基质细胞中的 LIFR 敲低则逆转了这些影响。ADT 驱动的 LIF/LIFR 信号传导诱导脑源性神经营养因子 (BDNF) 表达，进而促进 PCa 细胞的 NED、攻击性和免疫逃避。临床分析表明，转移性去势抵抗性前列腺癌 (CRPC) 中 BDNF 水平升高，并且与程序性死亡配体 1 (PDL1) 和免疫抑制特征呈正相关。这项研究表明，PCa 细胞和前列腺基质细胞之间的串扰增强了 LIF/LIFR 信号传导，通过上调 BDNF 导致 PCa 细胞中的免疫抑制 TME 和 NED。