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Research ArticleImmunology Free access | 10.1172/JCI32567

TNF-α is critical for antitumor but not antiviral T cell immunity in mice

Thomas Calzascia, Marc Pellegrini, Håkan Hall, Laurent Sabbagh, Nobuyuki Ono, Alisha R. Elford, Tak W. Mak, and Pamela S. Ohashi

The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.

Address correspondence to: Pamela S. Ohashi, Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Phone: (416) 946-2357; Fax: (416) 946-2086; E-mail: pohashi@uhnres.utoronto.ca.

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The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.

Address correspondence to: Pamela S. Ohashi, Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Phone: (416) 946-2357; Fax: (416) 946-2086; E-mail: pohashi@uhnres.utoronto.ca.

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The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.

Address correspondence to: Pamela S. Ohashi, Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Phone: (416) 946-2357; Fax: (416) 946-2086; E-mail: pohashi@uhnres.utoronto.ca.

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The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.

Address correspondence to: Pamela S. Ohashi, Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Phone: (416) 946-2357; Fax: (416) 946-2086; E-mail: pohashi@uhnres.utoronto.ca.

Find articles by Sabbagh, L. in: PubMed | Google Scholar

The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.

Address correspondence to: Pamela S. Ohashi, Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Phone: (416) 946-2357; Fax: (416) 946-2086; E-mail: pohashi@uhnres.utoronto.ca.

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The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.

Address correspondence to: Pamela S. Ohashi, Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Phone: (416) 946-2357; Fax: (416) 946-2086; E-mail: pohashi@uhnres.utoronto.ca.

Find articles by Elford, A. in: PubMed | Google Scholar

The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.

Address correspondence to: Pamela S. Ohashi, Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Phone: (416) 946-2357; Fax: (416) 946-2086; E-mail: pohashi@uhnres.utoronto.ca.

Find articles by Mak, T. in: PubMed | Google Scholar

The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Toronto, Ontario, Canada.

Address correspondence to: Pamela S. Ohashi, Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Departments of Medical Biophysics and Immunology, 610 University Avenue, Toronto, Ontario M5G 2M9, Canada. Phone: (416) 946-2357; Fax: (416) 946-2086; E-mail: pohashi@uhnres.utoronto.ca.

Find articles by Ohashi, P. in: PubMed | Google Scholar

Published November 8, 2007 - More info

J Clin Invest. https://doi.org/10.1172/JCI32567.
© 2007 The American Society for Clinical Investigation
Published November 8, 2007 - Version history
Received: May 2, 2007; Accepted: September 12, 2007
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Abstract

TNF-α antagonists are widely used in the treatment of inflammatory and autoimmune diseases, but their use is associated with reactivation of latent infections. This highlights the importance of TNF-α in immunity to certain pathogens and raises concerns that critical aspects of immune function are impaired in its absence. Unfortunately, the role of TNF-α in the regulation of T cell responses is clouded by a myriad of contradictory reports. Here, we show a role for TNF-α and its receptors, TNFR1 and TNFR2, specifically in antitumor immunity. TNF-α–deficient mice exhibited normal antiviral responses associated with strong inflammation. However, TNF-α/TNFR1–mediated signals on APCs and TNF-α/TNFR2 signals on T cells were critically required for effective priming, proliferation, and recruitment of tumor-specific T cells. Furthermore, in the absence of TNF-α signaling, tumor immune surveillance was severely abrogated. Finally, treatment with a CD40 agonist alone or in combination with TLR2 stimuli was able to rescue proliferation of TNF-α–deficient T cells. Therefore, TNF-α signaling may be required only for immune responses in conditions of limited immunostimulatory capacity, such as tumor surveillance. Importantly, these results suggest that prolonged continuous TNF-α blockade in patients may have long-term complications, including potential tumor development or progression.

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Version history
  • Version 1 (November 8, 2007): No description
  • Version 3 (December 3, 2007): No description
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