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The anti-tumor activity of anti-CTLA-4 is mediated through its induction of IFN gamma

T J Paradis1, E Floyd, J Burkwit

  • 1Department of Immunology, Central Research Division, Pfizer, Inc., Eastern Point Road, Groton, CT 06340, USA.

Cancer Immunology, Immunotherapy : CII
|June 23, 2001
PubMed

Insights

Blocking antibodies against CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) enhance anti-tumor immunity. This study reveals that CTLA-4 blockade boosts interferon-gamma (IFN-γ) production, crucial for tumor regression.

Area of Science:

  • Immunology
  • Cancer Biology
  • Oncology

Background:

  • CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) is a T-cell receptor that negatively regulates lymphocyte activation.
  • The anti-tumor effects of CTLA-4 blocking antibodies are known, but the underlying mechanisms remain unclear.
  • Interferon-gamma (IFN-γ) is a cytokine with known anti-tumor properties.

Purpose of the Study:

  • To investigate the role of IFN-γ in the anti-tumor activity of CTLA-4 blocking antibodies.
  • To elucidate the mechanisms by which CTLA-4 blockade mediates tumor regression.

Main Methods:

  • In vitro and in vivo experiments using tumor-bearing mice and fibrosarcoma models.
  • Measurement of IFN-γ production and IFN-γ-inducible enzyme (2-5-OAS) levels.
  • Assessment of tumor cell apoptosis and angiogenesis.
  • Utilized blocking and neutralizing antibodies against CTLA-4 and IFN-γ.

Main Results:

  • Anti-CTLA-4 treatment significantly increased IFN-γ production by lymph node cells in vitro.
  • Elevated levels of IFN-γ and the IFN-inducible enzyme 2-5-OAS were observed in tumor-bearing mice treated with anti-CTLA-4.
  • Neutralizing IFN-γ antibodies abrogated the anti-tumor effects of anti-CTLA-4.
  • Fibrosarcoma cells showed sensitivity to IFN-γ-mediated class I upregulation.
  • Tumors from anti-CTLA-4 treated mice exhibited increased apoptosis and decreased angiogenesis.

Conclusions:

  • IFN-γ plays a critical role in mediating the anti-tumor effects of CTLA-4 blockade.
  • CTLA-4 blockade enhances anti-tumor immunity by augmenting IFN-γ production.
  • This leads to increased tumor cell apoptosis and reduced angiogenesis, contributing to tumor regression.

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