Approaches to reverse interleukin-10 mediated immunosuppression in chronic lymphocytic leukemia

Abstract B cell Chronic Lymphocytic Leukemia (CLL), the most common leukemia in the western world, is characterized by an accumulation of abnormal B cells in the blood and lymphoid organs. Broad immunosuppression is a serious complication for these patients, with infections and secondary cancers recognized as the leading causes of morbidity and mortality. Although the immune suppression is in part due to clonotypic CLL B cells crowding immune organs, immune responses may also be suppressed by the production of soluble mediators. We and others found that CLL cells produce interleukin-10 (IL-10), a cytokine that suppresses T cell effector function. We hypothesized that this IL-10 may reduce anti-tumor T cell responses. In our studies we use human cells as well as the Eμ-Tcl1 mouse model for U-CLL, in which the oncogene Tcl1 is expressed under the immunoglobulin VH promoter and μ-enhancer. Previously, we found that IL-10R−/− T cells control CLL growth better than WT T cells in the Eμ-Tcl1 adoptive transfer model. We also saw that CLL IL-10 production is dependent on BCR signaling and activation of the transcription factor Sp-1. IL-10 production can be blocked by mithramycin (MTM), an Sp-1 inhibitor. However, MTM is not used routinely as an anti-cancer agent due to its short half-life and associated toxicities, so we prepared and tested novel analogues of MTM to reduce these effects. One of these analogues, MTM23, shows promise as it has similar potency to MTM, but does not interfere with T cell gamma-interferon production or viability. This approach is novel as current therapies for CLL do not target IL-10, or address the immunosuppression seen in CLL patients. IL-10 blockade could therefore be a strategy for harnessing anti-tumor T cells to treat CLL in humans.