BACKGROUND Tumor response to immunotherapy is the consequence of a concerted crosstalk between cytokines and effector cells. Interferon gamma (IFNγ) is one of the common cytokines coordinating tumor immune response and the associated biological consequences. Although the role of IFNγ in the modulation of tumor immunity has been widely documented, the mechanisms regulating IFNγ-induced cell death, during the course of immune therapy, is not described in detail. RESULTS IFNγ triggered apoptosis of CLS-354 and RPMI 2650 cells, enhanced the protein expression and activation of indoleamine 2,3-dioxygenase (IDO), and suppressed the basal expression of heme oxygenase-1(HO-1). Interestingly, IFNγ induced the loss of mitochondrial membrane potential (Δψm) and increased accumulation of reactive oxygen species (ROS). The cytokine also induced the activation of Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT)1, apoptosis signal-regulating kinase 1 (ASK1), p38, c-jun-N-terminal kinase (JNK) and NF-κB pathways and the transcription factors STAT1, interferon regulatory factor 1 (IRF1), AP-1, ATF-2, NF-κB and p53, and expression of Noxa protein. Furthermore, IFNγ was found to trigger endoplasmic reticulum (ER) stress as evidenced by the cleavage of caspase-4 and activation of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and inositol-requiring-1α (IRE1α) pathways. Using specific inhibitors, we identified a potential role for IDO as apoptotic mediator in the regulation of IFNγ-induced apoptosis of head and neck squamous cell carcinoma (HNSCC) cells via Noxa-mediated mitochondrial dysregulation and ER stress. CONCLUSION In addition to the elucidation of the role of IDO in the modulation of apoptosis, our study provides new insights into the molecular mechanisms of IFNγ-induced apoptosis of HNSCC cells during the course of immune therapy.

中文翻译：

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干扰素γ诱导的头颈部鳞状细胞癌凋亡通过线粒体和内质网应激相关途径与吲哚胺-2,3-二加氧酶连接。

背景技术对免疫疗法的肿瘤反应是细胞因子和效应细胞之间协同串扰的结果。干扰素γ（IFNγ）是协调肿瘤免疫应答和相关生物学后果的常见细胞因子之一。尽管已经广泛证明了IFNγ在调节肿瘤免疫力中的作用，但是在免疫治疗过程中调节IFNγ诱导的细胞死亡的机制并未详细描述。结果IFNγ可诱导CLS-354和RPMI 2650细胞凋亡，增强吲哚胺2,3-二加氧酶（IDO）的蛋白表达和活化，并抑制血红素加氧酶-1（HO-1）的基础表达。有趣的是，IFNγ引起线粒体膜电位（Δψm）的损失和活性氧（ROS）的积累。细胞因子还诱导Janus激酶（JAK）/信号转导子和转录激活子（STAT）1，细胞凋亡信号调节激酶1（ASK1），p38，c-jun-N-末端激酶（JNK）和NF- κB通路和转录因子STAT1，干扰素调节因子1（IRF1），AP-1，ATF-2，NF-κB和p53以及Noxa蛋白的表达。此外，发现IFNγ会触发内质网（ER）应激，这由caspase-4的裂解以及蛋白激酶RNA样内质网激酶（PERK）和需要肌醇的1α（IRE1α）途径的激活所证明。使用特定的抑制剂，我们确定了IDO作为细胞凋亡介体的潜在作用，它通过Noxa介导的线粒体失调和ER应激来调节IFNγ诱导的头颈部鳞状细胞癌（HNSCC）细胞凋亡。