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Combined inhibition of JAK12/Stat3-PD-L1 signaling pathway suppresses the immune escape of castration-resistant prostate cancer to NK cells in hypoxia

机译:联合抑制JAK12 / Stat3-PD-L1信号通路可抑制去势抵抗性前列腺癌在缺氧条件下对NK细胞的免疫逃逸

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摘要

Castration-resistant prostate cancer (CRPC) is difficult to treat in current clinical practice. Hypoxia is an important feature of the CRPC microenvironment and is closely associated with the progress of CRPC invasion. However, no research has been performed on the immune escape of CRPC from NK cells. The present study focused on this subject. Firstly, when the CRPC cell lines C4-2 and CWR22Rv1 were induced by hypoxia, the expression of the UL16 binding protein (ULBP) ligand family of natural killer (NK) group 2D (NKG2D; ULBP-1, ULBP-2 and ULBP-3) and MHC class I chain-related proteins A and B (MICA/MICB) decreased. NKG2D is the main activating receptor of NK cells. Tumor cells were then co-cultured with NK cells to conduct NK cell-mediated cytotoxicity experiments, which revealed the decreased immune cytolytic activity of NK cells on hypoxia-induced CRPC cells. In exploring the mechanism behind this observation, an increase in programmed death-ligand 1 (PD-L1) expression in CRPC cells induced by hypoxia was observed, while the addition of PD-L1 antibody effectively reversed the expression of NKG2D ligand and enhanced the cytotoxic effect of NK cells on CRPC cells. In the process of exploring the upstream regulatory factors of PD-L1, inhibition of the Janus kinase (JAK)1,2/signal transducer and activator of transcription 3 (Stat3) signaling pathway decreased the expression of PD-L1 in CRPC cells. Finally, it was observed that combined inhibition of JAK1,2/PD-L1 or Stat3/PD-L1 was more effective than inhibition of a single pathway in enhancing the immune cytolytic activity of NK cells. Taking these results together, it is thought that combined inhibition of the JAK1,2/PD-L1 and Stat3/PD-L1 signaling pathways may enhance the immune cytolytic activity of NK cells toward hypoxia-induced CRPC cells, which is expected to provide novel ideas and targets for the immunotherapy of CRPC.
机译:在当前的临床实践中,去势抵抗性前列腺癌(CRPC)难以治疗。缺氧是CRPC微环境的重要特征,并且与CRPC入侵的进展密切相关。然而,尚未进行关于CRPC从NK细胞的免疫逃逸的研究。目前的研究集中在这个问题上。首先,当缺氧诱导CRPC细胞系C4-2和CWR22Rv1时,自然杀手(NK)2D组(NKG2D; ULBP-1,ULBP-2和ULBP-)的UL16结合蛋白(ULBP)配体家族的表达3)和MHC I类链相关蛋白A和B(MICA / MICB)下降。 NKG2D是NK细胞的主要激活受体。然后将肿瘤细胞与NK细胞共培养以进行NK细胞介导的细胞毒性实验,该实验揭示了NK细胞对缺氧诱导的CRPC细胞的免疫溶细胞活性降低。在探索这一发现背后的机制时,观察到缺氧诱导的CRPC细胞中程序性死亡配体1(PD-L1)表达的增加,而添加PD-L1抗体则有效逆转了NKG2D配体的表达并增强了细胞毒性细胞对CRPC细胞的作用在探索PD-L1的上游调节因子的过程中,抑制Janus激酶(JAK)1,2 /信号转导子和转录激活因子3(Stat3)信号通路降低了PD-L1在CRPC细胞中的表达。最后,观察到JAK1,2 / PD-L1或Stat3 / PD-L1的联合抑制在增强NK细胞的免疫溶细胞活性方面比抑制单个途径更有效。综合这些结果,认为联合抑制JAK1,2 / PD-L1和Stat3 / PD-L1信号通路可以增强NK细胞对缺氧诱导的CRPC细胞的免疫溶细胞活性,有望提供新的CRPC免疫疗法的思路和目标。

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