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Sensitization of IL-2 Signaling through TLR-7 Enhances B Lymphoma Cell Immunogenicity¹

Jelena Tomic^*,, Dionne White^*, Yonghong Shi^*, Jenny Mena^*, Caitlin Hammond^*,, Liwei He^¶, Richard L. Miller^|| and David E. Spaner^2,*,,,

^* Division of Molecular and Cellular Biology, Research Institute, Sunnybrook and Women’s College Health Sciences Center, Toronto, Canada; Toronto-Sunnybrook Regional Cancer Center, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada; ^¶ Immunology Platform, Aventis Pasteur, Toronto, Canada; and ^|| Department of Pharmacology, 3M Pharmaceuticals, St. Paul, MN 55144

The innate ability of B lymphoma cells to escape control by tumor-reactive T cells must be overcome to develop effective immunotherapies for these diseases. Because signals from both the innate and adaptive immune systems direct the acquisition of strong immunogenicity by professional APCs, the effects of IL-2 and the TLR-7 agonist, S28690, on the immunogenic properties of chronic lymphocytic leukemia (CLL) B cells were studied. IL-2 with S28690 caused CLL cells to proliferate and increased their expression of B7-family members, production of TNF- and IL-10, and levels of tyrosine-phosphorylated STAT-1 and STAT-3 proteins. S28690 increased CD25 expression on CLL cells and sensitized them to IL-2 signaling. However, IL-2 did not change TLR-7 expression or signaling in CLL cells. The ability to stimulate T cell proliferation required additional activation of protein kinase C, which inhibited tumor cell proliferation, "switched off" IL-10 production, and caused essentially all CLL cells (regardless of clinical stage) to acquire a CD83^highCD80^highCD86^highCD54^high surface phenotype marked by the activation of STAT-1 without STAT-3. These findings suggest that TLR-7 "licenses" human B cells to respond to cytokines of the adaptive immune system (such as IL-2) and provide a strategy to increase the immunogenicity of lymphoma cells for therapeutic purposes.

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