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

Abstract

BackgroundTumor 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.ResultsIFNγ 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.ConclusionIn 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.

Composition and Clinical Impact of the Immunologic Tumor Microenvironment in Oral Squamous Cell Carcinoma

“…The main focus of our present study was therefore to further delineate the morphologic phenotype of the immunologic tumor-host interaction in OSCC as described in the cancer immunity cycle (15,20), in particular to exactly describe the composition of the inflammatory infiltrate involved in cell-mediated immunity, composed by various subsets of T cells (CD3 + T cells; CD4 + T cells; CD8 + T killer cells; CD4 + FOXP3 + Tregs; IL-17A + Th17 cells) and its association with HLA class I expression, IFN-g expression, and morphology, taking into account spatial heterogeneity of immunologic parameters (stroma versus epithelial infiltrate; IF versus TCe). As previously described, the immune cell infiltrate as well as HLA class I and IFN-g play an important role in head and neck squamous cell carcinoma (26,27,36,38,51,52). Confirming these findings, we found a strong positive association of high intraepithelial and stromal CD3 + , CD4 + , CD8 + , CD4 + FOXP3 + , and IL-17A + inflammatory infiltrate not only with each other but also with high HLA class I and presence of IFN-g expression in TILs.…”

Altered expression of TIM‐3, LAG‐3, IDO, PD‐L1, and CTLA‐4 during nimotuzumab therapy correlates with responses and prognosis of oral squamous cell carcinoma patients

“…PD‐1 and CTLA‐4 are the most studied checkpoint target molecules, and PD‐L1 expression is reported as a predictive biomarker in cancer immunotherapy . LAG‐3 and TIM3 are the next promising inhibitory checkpoints to be translated to the clinic, are highly expressed on exhausted or dysfunctional T cells in infection and cancer . Blockade of IDO‐1 combined with checkpoint receptors has been found to induce prominent antitumor responses in various solid tumors .…”

“…18 LAG-3 and TIM3 are the next promising inhibitory checkpoints to be translated to the clinic, are highly expressed on exhausted or dysfunctional T cells in infection and cancer. 19,20 Blockade of IDO-1 combined with checkpoint receptors has been found to induce prominent antitumor responses in various solid tumors. 21 Previous study has reported that PD-1 + and TIM-3 + tumorinfiltrating lymphocytes were increased after cetuximab therapy in HNSCC patients, and the increased frequency of PD-1 + and TIM-3 + TILs was inversely correlated with clinical outcome of cetuximab therapy.…”

A gene signature associated with prognosis and immune processes in head and neck squamous cell carcinoma

“…The tumor response to immunotherapy is a consequence of a concerted crosstalk between cytokines and effector cells . IFN‐γ is one of the central cytokines that coordinates tumor immune responses and the associated biological consequences and shows antitumor activity combined with IDO in patients with non‐small‐cell lung carcinoma and in HNSCC cell lines . The PD‐1:PD‐L1/PD‐L2 pathway has been implicated in tumor escape from immune destruction in various cancers .…”