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bioRxiv · 10.1101/517003

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

Zhang, Y.·Song, M.·Ping, Y.·Zhang, K.·Yang, L.·Li, F.·Cheng, S.·Yue, D.·Maimela, N. R.·Qu, J.·Liu, S.·Sun, T.·Li, Z.·Xia, J.·Zhang, B.·Wang, L.
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Abstract

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

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Zhang, Y., Song, M., Ping, Y., Zhang, K., Yang, L., Li, F., Cheng, S., Yue, D., Maimela, N. R., Qu, J., Liu, S., Sun, T., Li, Z., Xia, J., Zhang, B., Wang, L.. 2019-01-11. Low-dose IFN-γ induces tumor cell stemness in tumor microenvironment of non-small cell lung cancer. https://doi.org/10.1101/517003

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