Sustained low-level expression of interferon-γ promotes tumor development : potential insights in tumor prevention and tumor immunotherapy

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2005-09, Vol.54 (9), p.891-897
• Main Authors: HE, Yu-Fei, WANG, Xiao-Hong, ZHANG, Gui-Mei, CHEN, Hong-Tao, HUI ZHANG, FENG, Zuo-Hua
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - immunology; Adenocarcinoma - metabolism; Adenocarcinoma - prevention & control; Animals; Antigens, CD; Antigens, Differentiation - metabolism; Antineoplastic agents; Antineoplastic Agents - immunology; Antineoplastic Agents - metabolism; B7-1 Antigen - metabolism; B7-H1 Antigen; Biological and medical sciences; Carcinoma, Hepatocellular - immunology; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - prevention & control; CTLA-4 Antigen; DNA-Binding Proteins - metabolism; Female; Forkhead Transcription Factors; Immunotherapy; Interferon-gamma - physiology; Liver Neoplasms - immunology; Liver Neoplasms - metabolism; Liver Neoplasms - prevention & control; Mammary Neoplasms, Experimental - immunology; Mammary Neoplasms, Experimental - metabolism; Mammary Neoplasms, Experimental - prevention & control; Medical sciences; Melanoma, Experimental - immunology; Melanoma, Experimental - metabolism; Melanoma, Experimental - prevention & control; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred BALB C; Muscles - immunology; Muscles - metabolism; Original; Peptides - metabolism; Pharmacology. Drug treatments; Programmed Cell Death 1 Ligand 2 Protein; Skin Neoplasms - immunology; Skin Neoplasms - metabolism; Skin Neoplasms - prevention & control; T-Lymphocytes, Cytotoxic; Tumor Cells, Cultured; Tumor Escape - genetics; Tumor Escape - immunology
• ISSN: 0340-7004; 1432-0851; 1365-2567
• DOI: 10.1007/s00262-004-0654-1

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.