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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.

Author information

1
First Affiliated Hospital of Zhengzhou University.
2
Biotherapy Center, First Affiliated Hospital of Zhengzhou University.
3
Biotherapy center, Biotherapy Center, the First Affiliated Hospital of Zhengzhou University.
4
Oncology, First Affiliated Hospital of Zhengzhou University.
5
Institute for Immuno-Oncology, The Ohio State University.
6
State Key Laboratory of Oncology, Sun Yat-sen University Cancer Center.
7
Medicine, Northwestern University.
8
Biotherapy Center and Cancer Center, First Affiliated Hospital of Zhengzhou University yizhang@zzu.edu.cn.

Abstract

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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