Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / immunology
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Adenocarcinoma / metabolism
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Adenocarcinoma / prevention & control
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Animals
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Antigens, CD
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Antigens, Differentiation / metabolism
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Antineoplastic Agents / immunology
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Antineoplastic Agents / metabolism*
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B7-1 Antigen / metabolism
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B7-H1 Antigen
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CTLA-4 Antigen
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Carcinoma, Hepatocellular* / immunology
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Carcinoma, Hepatocellular* / metabolism
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Carcinoma, Hepatocellular* / prevention & control
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DNA-Binding Proteins / metabolism
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Female
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Forkhead Transcription Factors
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Immunotherapy*
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Interferon-gamma / physiology*
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Liver Neoplasms / immunology
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Liver Neoplasms / metabolism
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Liver Neoplasms / prevention & control
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Mammary Neoplasms, Experimental* / immunology
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Mammary Neoplasms, Experimental* / metabolism
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Mammary Neoplasms, Experimental* / prevention & control
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Melanoma, Experimental* / immunology
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Melanoma, Experimental* / metabolism
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Melanoma, Experimental* / prevention & control
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Membrane Glycoproteins / metabolism
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Mice
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Mice, Inbred BALB C
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Muscles / immunology
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Muscles / metabolism
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Peptides / metabolism
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Programmed Cell Death 1 Ligand 2 Protein
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Skin Neoplasms / immunology
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Skin Neoplasms / metabolism
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Skin Neoplasms / prevention & control
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T-Lymphocytes, Cytotoxic
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Tumor Cells, Cultured
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Tumor Escape / genetics
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Tumor Escape / immunology*
Substances
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Antigens, CD
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Antigens, Differentiation
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Antineoplastic Agents
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B7-1 Antigen
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B7-H1 Antigen
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CTLA-4 Antigen
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Cd274 protein, mouse
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Ctla4 protein, mouse
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DNA-Binding Proteins
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Membrane Glycoproteins
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Pdcd1lg2 protein, mouse
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Peptides
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Programmed Cell Death 1 Ligand 2 Protein
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Interferon-gamma