Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation

French, Ruth R., Taraban, Vadim Y., Crowther, Graham R., Rowley, Tania F., Gray, Juliet C., Johnson, Peter W., Tutt, Alison L., Al-Shamkhani, Aymen and Glennie, Martin J. (2007) Eradication of lymphoma by CD8 T cells following anti-CD40 monoclonal antibody therapy is critically dependent on CD27 costimulation. Blood, 109 (11), 4810-4815. (doi:10.1182/blood-2006-11-057216).

Abstract

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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Contributors

Author: Juliet C. Gray

Author: Peter W. Johnson

Author: Aymen Al-Shamkhani

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