免疫环境在各种类型的癌症中起着重要作用。本研究重点关注Th1细胞因子对小儿急性淋巴细胞白血病（ALL）的影响。分析ALL细胞系和患者衍生异种移植模型（PDX）对Th1细胞因子TNF-α（肿瘤坏死因子α）和IFN-γ（干扰素γ）的反应，并与相应的细胞因子受体和细胞内信号分子进行相关性分析。ALL细胞系和ALL PDX在与TNF-α和IFN-γ孵育后表现出极大的细胞死亡异质性。一些样本显示出双因子剂量依赖性和加性诱导细胞死亡的效应；而其他样本则没有任何反应，甚至显示出增强的存活能力。凋亡是Th1细胞因子在ALL细胞中主要引起的细胞死亡方式。在所有分析的白血病细胞中，IFN-γ受体（IFNGR）的表达高于两种TNF受体，导致与TNF信号通路相比，STAT1（信号转导和转录激活因子-1）的磷酸化水平较高的NF-κB（核因子kappa-B的轻链增强因子）磷酸化水平。STAT1的激活与Th1细胞因子刺激后细胞死亡的数量相关。TNF-α和IFN-γ在ALL细胞系和ALL PDX中引起异质反应，但能够在大多数ALL爆发细胞中通过凋亡诱导细胞死亡。IFNGR的高表达和随之发生的STAT1的激活与细胞死亡的相关性表明IFN-γ信号在这种情况下起着重要作用。© 2023. 作者(们)。

Immune milieus play an important role in various types of cancer. The present study focuses on the effect of Th1 cytokines on pediatric acute lymphoblastic leukemia (ALL). The reaction of ALL cell lines and patient-derived xenografts (PDX) to the most important Th1 cytokines TNF-α (tumor necrosis factor alpha) and IFN-γ (interferon gamma) is analyzed and correlated with the respective cytokine receptors and the intracellular signaling molecules. ALL cell lines and ALL PDX display a great heterogeneity in cell death after incubation with TNF-α and IFN-γ. Several samples show a dose-dependent and additive induction of cell death by both cytokines; others do not react at all or even display an increased viability. Apoptosis is the main type of cell death induced by Th1 cytokines in ALL cells. Over all leukemia cells analyzed, IFN-γ receptor (IFNGR) shows a higher expression than both TNF-receptors, resulting in higher phosphorylation of STAT1 (signal transducer and activator of transcription) compared to phosphorylation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B-cells) in the TNF pathway. The activation of STAT1 correlates with the amount of cell death after stimulation with Th1 cytokines. TNF-α and IFN-γ lead to heterogeneous reactions in ALL cell lines and ALL PDX but are able to induce cell death by apoptosis in the majority of ALL blasts. The correlation of a high expression of IFNGR and following activation of STAT1 with cell death indicates an important role for IFN-γ signaling in this setting.© 2023. The Author(s).