Low-Dose IFNγ Induces Tumor Cell Stemness in Tumor Microenvironment of Non-Small Cell Lung Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 14; pp. 3737 - 3748
• Main Authors: Song, Mengjia, Ping, Yu, Zhang, Kai, Yang, Li, Li, Feng, Zhang, Chaoqi, Cheng, Shaoyan, Yue, Dongli, Maimela, Nomathamsanqa Resegofetse, Qu, Jiao, Liu, Shasha, Sun, Ting, Li, Zihai, Xia, Jianchuan, Zhang, Bin, Wang, Liping, Zhang, Yi
• Format: Journal Article
• Language: English
• Published: United States 15.07.2019
• Subjects: A549 Cells; Animals; Apoptosis - drug effects; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Caspases - metabolism; Cell Line, Tumor; Dose-Response Relationship, Drug; Female; Humans; Intercellular Adhesion Molecule-1 - metabolism; Interferon-gamma - administration & dosage; Janus Kinase 1 - metabolism; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptor, Notch1 - metabolism; Recombinant Proteins - pharmacology; Signal Transduction - drug effects; STAT1 Transcription Factor - metabolism; Tumor Microenvironment - drug effects; Xenograft Model Antitumor Assays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-19-0596

IFNγ is conventionally recognized as an inflammatory cytokine that plays a central role in antitumor immunity. Although it has been used clinically to treat a variety of malignancies, low levels of IFNγ in the tumor microenvironment (TME) increase the risk of tumor metastasis during immunotherapy. Accumulating evidence suggests that IFNγ can induce cancer progression, yet the mechanisms underlying the controversial role of IFNγ in tumor development remain unclear. Here, we reveal a dose-dependent effect of IFNγ in inducing tumor stemness to accelerate cancer progression in patients with a variety of cancer types. Low levels of IFNγ endowed cancer stem-like properties via the intercellular adhesion molecule-1 (ICAM1)-PI3K-Akt-Notch1 axis, whereas high levels of IFNγ activated the JAK1-STAT1-caspase pathway to induce apoptosis in non-small cell lung cancer (NSCLC). Inhibition of ICAM1 abrogated the stem-like properties of NSCLC cells induced by the low dose of IFNγ both and . This study unveils the role of low levels of IFNγ in conferring tumor stemness and elucidates the distinct signaling pathways activated by IFNγ in a dose-dependent manner, thus providing new insights into cancer treatment, particularly for patients with low expression of IFNγ in the TME. SIGNIFICANCE: These findings reveal the dose-dependent effect of IFNγ in inducing tumor stemness and elucidate the distinct molecular mechanisms activated by IFNγ in a dose-dependent manner.