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Low-dose IFN-γ induces tumor cell stemness in tumor microenvironment of non-small cell lung cancer

By Mengjia Song, Yu Ping, Kai Zhang, Li Yang, Feng Li, Shaoyan Cheng, Dongli Yue, Nomathamsanqa Resegofetse Maimela, Jiao Qu, Shasha Liu, Ting Sun, Zihai Li, Jianchuan Xia, Bin Zhang, Liping Wang, Yi Zhang

Posted 11 Jan 2019
bioRxiv DOI: 10.1101/517003

Interferon-γ (IFN-γ) is conventionally recognized as an antitumor cytokine. Clinically, although has been used clinically to treat a variety of malignancies, low-level IFN-γ in the tumor microenvironment (TME) increases the risk of tumor metastasis during immunotherapy. Accumulating evidence has suggested that IFN-γ can induce cancer progression. The mechanisms underlying the controversial role of IFN-γ regulating tumor development remain unclear. Herein, we firstly revealed a dose-dependent effect of IFN-γ in inducing tumor stemness in patients with a variety of cancer types. Mechanically, low-level IFN-γ endowed cancer stem-like properties via the intercellular adhesion molecule-1 (ICAM1)-PI3K-Akt-Notch1 axis, whereas high-level IFN-γ 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 IFN-γ both in vitro and in vivo. Our study first defines the role of low-level IFN-γ in conferring tumor stemness and clearly elucidate the distinct signaling pathways activated by IFN-γ in a dose-dependent manner, providing new insights into cancer treatment, particularly patients with low-level IFN-γ expression in the TME.

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