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Cancer Res. 2019 May 13. pii: canres.0596.2019. doi: 10.1158/0008-5472.CAN-19-0596. [Epub ahead of print]

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

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First Affiliated Hospital of Zhengzhou University.
Biotherapy Center, First Affiliated Hospital of Zhengzhou University.
Biotherapy center, Biotherapy Center, the First Affiliated Hospital of Zhengzhou University.
Oncology, First Affiliated Hospital of Zhengzhou University.
Institute for Immuno-Oncology, The Ohio State University.
State Key Laboratory of Oncology, Sun Yat-sen University Cancer Center.
Medicine, Northwestern University.
Biotherapy Center and Cancer Center, First Affiliated Hospital of Zhengzhou University


Interferon-γ (IFN-γ) 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 IFN-γ in the tumor microenvironment (TME) increase the risk of tumor metastasis during immunotherapy. Accumulating evidence suggests that IFN-γ can induce cancer progression, yet the mechanisms underlying the controversial role of IFN-γ in tumor development remain unclear. Here we reveal a dose-dependent effect of IFN-γ in inducing tumor stemness to accelerate cancer progression in patients with a variety of cancer types. Low levels of IFN-γ endowed cancer stem-like properties via the intercellular adhesion molecule-1 (ICAM1)-PI3K-Akt-Notch1 axis, whereas high levels of 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. This study unveils the role of low levels of IFN-γ in conferring tumor stemness and elucidates the distinct signaling pathways activated by IFN-γ in a dose-dependent manner, thus providing new insights into cancer treatment, particularly for patients with low expression of IFN-γ in the TME.

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