1. Department of Gynecology of Integrated Traditional Chinese and Western Medicine, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200011, People's Republic of China
2. Department of Obstetrics and Gynecology, Zhangye People's Hospital of HeXi College, Zhangye, Gansu, 734000, China
3. Laboratory for Reproductive Immunology, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai, 200011, People's Republic of China
4. Key Laboratory of Reproduction Regulation of NPFPC, SIPPR, IRD, Fudan University, Shanghai 200032, People's Republic of China
5. Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, 200011, People's Republic of China
*Shao-Liang Yang and Hai-Xia Tan contributed equally to this work.
Background: Cervical cancer is a common malignant disease in female patients accompanied by activation of autophagy in tumor cells. However, the exact regulatory factors of autophagy and its effects on the immune response remain unknown.
Methods: The induction of autophagy in HeLa and SiHa cells treated with IFN-γ, tryptophan depletion, kynurenine and epacadostat was detected by western blot analysis and by an autophagy detection kit. Following co-culture with pre-treated HeLa and SiHa cells, U937 cells were analyzed by flow cytometry to detect CD80, CD86, CD163 and CD206 expression and the induction of phagocytosis.
Results: IFN-γ caused a significant increase in the autophagy levels of HeLa and SiHa cells by promoting indoleamine-2,3-dioxygenase-1 (IDO1) expression. The induction of phagocytosis in HeLa and SiHa cells and the expression levels of CD80 and CD86 in U937 cells were increased significantly following treatment with recombinant human IFN-γ. This effect was associated with the induction of tumor cell autophagy. IFN-γ treatment and IDO1 overexpression promoted tryptophan depletion and kynurenine accumulation in cervical cancer cells. The latter was more potent in inducing autophagy of cervical cancer cells and promoting phagocytosis of macrophages. In vivo, IDO1 overexpression restricted tumor growth in C57 mice and enhanced the induction of phagocytosis in macrophages.
Conclusions: IFN-γ promoted induction of autophagy and macrophage phagocytosis in cervical cancer cells possibly via IDO1 expression and kynurenine metabolism.
Keywords: IFN-γ, IDO1, kynurenine, autophagy, cervical cancer, phagocytosis, macrophage