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

Mengjia Song, Yu Ping, Kai Zhang, Li Yang, Feng Li, Chaoqi Zhang, Shaoyan Cheng, Dongli Yue, Nomathamsanqa Resegofetse Maimela, Jiao Qu, Shasha Liu, Ting Sun (+5 others)
2019 Cancer Research  
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
more » ... veal 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 in vitro and in vivo. 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.
doi:10.1158/0008-5472.can-19-0596 pmid:31085700 fatcat:tst5jeuponhq3jcex6jnlz6piu