Dysfunctional T Regulatory Cells in Myeloma: Molecular Mechanisms of Dysregulation.

Multiple myeloma (MM) is characterized by production of monoclonal immunoglobulin, associated with suppressed uninvolved immunoglobulins and dysfunctional T cell responses. The biological basis of this dysfunction remains ill defined. Since T regulatory (T_reg) cells play an important role in suppressing normal immune responses, we have here evaluated the potential role of T_reg cells in immune dysfunction in MM. We observed a significant increase in CD4⁺CD25⁺ T cells in individuals with monoclonal gammopathy of undetermined significance (MGUS) and patients with MM compared to normal donors (25% and 26% versus 14%, respectively); however, T_reg cells as measured by Foxp3 expression are significantly decreased in both MGUS (1.6±0.5%, p<0.01) and MM (1.6±0.5%, p<0.01) compared to normal donors (6.0±0.8%). Additionally, these T_reg cells also do not function normally. T_reg cells from patients with MM and MGUS even when added in higher proportions are unable to suppress anti-CD3-mediated T cell proliferation. This decreased number and function of T_reg cells in MGUS and in MM may account, at least in part, for the non-specific increase in CD4⁺CD25⁺ T cells, thereby contributing to dysfunctional T cell responses. We have further analyzed the molecular basis for the T_reg cell dysfunction in myeloma. Based on the preliminary results suggesting a role of IL-6 in T_reg cell function and since both serum IL-6 and soluble IL-6 receptor levels are significantly elevated in MGUS and MM, we evaluated the role of IL-6 and its soluble receptor on T_reg cell function. We observed that the addition of IL-6 and/or sIL-6 receptor to the culture leads to loss of T_reg cell activity in normal donor cells similar to one observed in myeloma patients; and conversely, when T_reg cells from MM patients are treated with the anti-IL-6 antibody or IL-6 receptor super antagonist, sant 7, the suppressive activity of T_reg cells is restored. Additionally, we have preliminary evidence of expansion of Foxp3⁺ cell numbers in PBMC from MM patients following in vitro treatment with anti-IL-6 antibody. This data suggests a role of IL-6 and bone marrow microenvironment in dysfunctional T_reg cells in MM and that inhibition of IL-6 signaling results in beneficial effects on T cell activity by increasing T_reg cell activity. A blockade of IL-6 signaling thus emerges as a potential approach to establish immune homeostasis to improve immune function in MM.