Sustained low-level expression of interferon-gamma promotes tumor development: potential insights in tumor prevention and tumor immunotherapy.
Although the proinflammatory cytokine interferon-gamma (IFN-gamma) has been generally thought to enhance antitumor immune responses and be involved in antitumor mechanisms of many other immunotherapy molecules, it has also been reported that IFN-gamma could promote tumor immune evasion. In this report, by using an ideal mouse model that expresses IFN-gamma locally in muscle, we demonstrate that sustained low-level expression of IFN-gamma promotes the development of several types of tumor including H22 hepatoma, MA782/5S mammary adenocarcinoma and B16 melanoma. However, transitory expression of IFN-gamma does not have such an effect. On the other hand, sustained high-level expression of IFN-gamma mediates significant antitumor effect on H22 hepatoma. Low level of IFN-gamma upregulates expression of PD-L1, PD-L2, CTLA-4 and Foxp3, which may partly account for the tumor immune evasion promoted by IFN-gamma. Furthermore, blockade of PD-L inhibits IFN-gamma's tumor-promoting effect. Our findings provide a mechanistic link between chronic inflammation and cancer and would have potential implications for cancer prevention and also for the design of cytokine-based cancer immunotherapy.
He
Yu-Fei
YF
Department of Biochemistry and Molecular Biology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, The People's Republic of China.
Wang
Xiao-Hong
XH
Zhang
Gui-Mei
GM
Chen
Hong-Tao
HT
Zhang
Hui
H
Feng
Zuo-Hua
ZH
D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D000970:Antineoplastic Agents / Q000276:immunology / Q000378:metabolism*; D018122:B7-1 Antigen / Q000378:metabolism; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors; D007167:Immunotherapy; D007371:Interferon-gamma / Q000502:physiology*; D008113:Liver Neoplasms / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D008546:Melanoma, Experimental / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009132:Muscles / Q000276:immunology / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D061027:Programmed Cell Death 1 Ligand 2 Protein; D012878:Skin Neoplasms / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control; D013602:T-Lymphocytes, Cytotoxic; D014407:Tumor Cells, Cultured; D019139:Tumor Escape / Q000235:genetics / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000970:Antineoplastic Agents; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; C498919:Cd274 protein, mouse; C556707:Ctla4 protein, mouse; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D008562:Membrane Glycoproteins; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D007371:Interferon-gamma