Interferon gamma-induced apoptosis of head and neck squamous cell carcinoma is connected to indoleamine-2,3-dioxygenase via mitochondrial and ER stress-associated pathways

Background: Tumor response to immunotherapy is the consequence of a concerted crosstalk between cytokines and effector cells. Interferon gamma (IFN gamma) is one of the common cytokines coordinating tumor immune response and the associated biological consequences. Although the role of IFN gamma in the modulation of tumor immunity has been widely documented, the mechanisms regulating IFN gamma-induced cell death, during the course of immune therapy, is not described in detail. Results: IFN gamma 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, IFN gamma induced the loss of mitochondrial membrane potential (Delta psi m) 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-kappa B pathways and the transcription factors STAT1, interferon regulatory factor 1 (IRF1), AP-1, ATF-2, NF-kappa B and p53, and expression of Noxa protein. Furthermore, IFN gamma 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-1 alpha (IRE1 alpha) pathways. Using specific inhibitors, we identified a potential role for IDO as apoptotic mediator in the regulation of IFN gamma-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 IFN gamma-induced apoptosis of HNSCC cells during the course of immune therapy.