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Blood, 1 June 2007, Vol. 109, No. 11, pp. 4810-4815.
Prepublished online as a Blood First Edition Paper on February 20, 2007; DOI 10.1182/blood-2006-11-057216.
Previous Article | Next Article 
Submitted November 17, 2006
Accepted February 13, 2007
Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation
Ruth R French, Vadim Y Taraban, Graham R Crowther, Tania F Rowley, Juliet C Gray, Peter W Johnson, Alison L Tutt, Aymen Al-Shamkhani, and Martin J Glennie*
Tenovus Research Laboratory, Cancer Sciences Division, School of Medicine, University General Hospital, Southampton, United Kingdom
* Corresponding author; email: mjg{at}soton.ac.uk.
Growing evidence points to the potential of agonistic anti-CD40 mAb as adjuvants for vaccination against cancer. These appear to act by maturing DC and allowing them to prime CD8 cytotoxic T lymphocytes (CTL). While it is well established that optimal T-cell priming requires co-stimulation via B7:CD28, recent studies emphasize the contribution of TNF receptors to this process. To understand how anti-CD40 mAb triggers effective anti-tumor immunity we investigated the role of TNFR superfamily members CD27 and 4-1BB in the generation of this immunity and showed that, while partially dependent on 4-1BB:4-1BBL engagement, it is completely reliant on CD27:CD70 interactions. Importantly, blocking CD70, and to some extent 4-1BBL, during anti-CD40 treatment, prevented accumulation of tumor reactive T cells and subsequent tumor protection. However, it did not influence changes in DC number, phenotype, nor the activity of CTL once immunity was established. We conclude that CD27:CD70 and 4-1BB:4-1BBL interactions are needed for DC-driven accumulation of anti-tumor CTL following anti-CD40 mAb treatment. Finally, in support of the critical role for CD70:CD27, we show for the first time that agonistic anti-CD27 mAb given without a DC maturation signal completely protect tumor-bearing mice and provides a highly potent reagent for boosting anti-tumor T cell immunity.

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