TNF-[alpha] is critical for antitumor but not antiviral T cell immunity in mice

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From: Journal of Clinical Investigation(Vol. 117, Issue 12)
Publisher: American Society for Clinical Investigation
Document Type: Article
Length: 9,067 words
Lexile Measure: 1460L

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Abstract :

TNF-[alpha] 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-[alpha] in immunity to certain pathogens and raises concerns that critical aspects of immune function are impaired in its absence. Unfortunately, the role of TNF-[alpha] in the regulation of T cell responses is clouded by a myriad of contradictory reports. Here, we show a role for TNF-[alpha] and its receptors, TNFR1 and TNFR2, specifically in antitumor immunity. TNF-[alpha]-deficient mice exhibited normal antiviral responses associated with strong inflammation. However, TNF-[alpha]/TNFR1-mediated signals on APCs and TNF-[alpha]/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-[alpha] 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-[alpha]-deficient T cells. Therefore, TNF-[alpha] 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-[alpha] blockade in patients may have long-term complications, including potential tumor development or progression.

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Gale Document Number: GALE|A172599251