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

Cancer Immunol Immunother. 2005 Sep;54(9):891-7. doi: 10.1007/s00262-004-0654-1. Epub 2005 Mar 18.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / prevention & control
  • Animals
  • Antigens, CD
  • Antigens, Differentiation / metabolism
  • Antineoplastic Agents / immunology
  • Antineoplastic Agents / metabolism*
  • B7-1 Antigen / metabolism
  • B7-H1 Antigen
  • CTLA-4 Antigen
  • Carcinoma, Hepatocellular* / immunology
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / prevention & control
  • 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
  • Melanoma, Experimental* / immunology
  • Melanoma, Experimental* / metabolism
  • Melanoma, Experimental* / prevention & control
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Muscles / immunology
  • Muscles / metabolism
  • Peptides / metabolism
  • 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*

Substances

  • Antigens, CD
  • Antigens, Differentiation
  • Antineoplastic Agents
  • B7-1 Antigen
  • B7-H1 Antigen
  • CTLA-4 Antigen
  • Cd274 protein, mouse
  • Ctla4 protein, mouse
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Membrane Glycoproteins
  • Pdcd1lg2 protein, mouse
  • Peptides
  • Programmed Cell Death 1 Ligand 2 Protein
  • Interferon-gamma