Induction of immunosuppressive molecules and regulatory T cells counteracts the antitumor effect of interleukin-12-based gene therapy in a transgenic mouse model of liver cancer

J Hepatol. 2007 Dec;47(6):807-15. doi: 10.1016/j.jhep.2007.07.025. Epub 2007 Oct 1.

Abstract

Background/aims: Hepatocellular carcinoma (HCC) often lacks curative treatment; therefore new efficient therapies are needed. In this work we aimed at evaluating the antitumor effect of interleukin-12 (IL-12)-based gene therapy on HCC occurring spontaneously in mice.

Methods: A plasmid-vector expressing IL-12 in a liver-specific and doxycycline (Dox)-inducible manner was transferred by hydrodynamic injection to the liver of L-PK/c-myc mice with HCC. IL-12 expression was induced by administering Dox (3 cycles of 1 month duration separated by 1 month rest).

Results: Dox administration increased serum IL-12 and IFN-gamma and induced tumor lymphocytic infiltration in all treated mice which was accompanied by tumor stabilization or regression in 40% of animals. The antitumor effect did not correlate with levels of IL-12 or IFN-gamma nor with the intensity of tumor mononuclear infiltration. However, tumors from non-responder mice showed more abundance of Foxp3+ regulatory T cells and higher expression of the immunosuppressive molecules PD-1, PD-L1, VEGF, CTLA-4, IDO, and IL-10 than those that responded to therapy.

Conclusions: Although long-term induction of IL-12 expression in the liver can inhibit HCC growth, the efficacy of the treatment appears to be limited by the activation of immunosuppressive mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemotaxis, Leukocyte
  • Doxycycline / pharmacology
  • Gene Expression Regulation / drug effects
  • Genetic Therapy / methods*
  • Immunologic Factors / genetics
  • Interferon-gamma / blood
  • Interleukin-12 / administration & dosage*
  • Interleukin-12 / blood
  • Liver Neoplasms / immunology
  • Liver Neoplasms / therapy*
  • Lymphocytes
  • Mice
  • Mice, Transgenic
  • Plasmids
  • T-Lymphocytes, Regulatory
  • Treatment Outcome
  • Tumor Burden

Substances

  • Immunologic Factors
  • Interleukin-12
  • Interferon-gamma
  • Doxycycline