PDF(Pubmed)
Abstract：
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.
摘要：
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）中的免疫逃避中起着至关重要的作用。虽然这些细胞对建立免疫抑制反应和影响PCa侵袭性的影响仍未完全理解。我们的研究表明，在前列腺肿瘤和基质细胞中，白血病抑制因子（LIF）/LIF受体（LIFR）通路的激活，雄激素剥夺治疗（ADT）后，导致免疫抑制性TME的发展。PCa细胞中LIF/LIFR信号的激活诱导神经内分泌分化(NED)并上调免疫检查点表达。LIF/LIFR的抑制减弱了这些影响，强调LIF/LIFR在将NED与免疫抑制联系起来中的关键作用。表达LIFR的前列腺基质细胞有助于PCa细胞中的NED和免疫抑制标志物丰度，而前列腺基质细胞中的LIFR敲除逆转了这些作用。ADT驱动的LIF/LIFR信号诱导脑源性神经营养因子（BDNF）表达，which,反过来,推广NED,侵略性,和PCa细胞的免疫逃避。临床分析表明，转移性去势抗性PCa（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细胞与前列腺基质细胞之间的串扰增强了LIF/LIFR信号，通过上调BDNF有助于PCa细胞中的免疫抑制性TME和NED。
