Multiple myeloma and immunomodulation: regulating the regulatory cells

Immune homeostasis is preserved by a balance between the eff ector and regulatory immune mechanisms. During cancer progression this balance is skewed toward immune tolerization, facilitating the tumor cells to escape the antitumor immune responses of the host. It is suggested that this immune evasion can be eff ectively reversed by immunomodulatory agents (IMiDs) such as lenalidomide [1]. Lenalidomide has antitumor activity in various hematologic cancers (including multiple myeloma, chronic lymphocytic leukemia, lymphomas and myelodysplastic syndromes) independent of the type or origin of the malignant cell [2]. Preclinical evaluations identifi ed its ability to modulate the immunological microenvironment both via cellular activation of the eff ector T and natural killer (NK) cells and by down-regulation of critical tumor supporting and immune suppressive cytokines (interleukin-6, tumor necrosis factor- α and vascular endothelial growth factor) in the tumor microenvironment [3]. In addition, it aff ects antigenpresenting cell function and the humoral immune response mediated through antibody-dependent cell-mediated cytotoxicity. Th e immune modulatory actions of lenalidomide aptly include both the eff ector T cells and regulatory T cells (Tregs). While the action of lenalidomide on eff ector T cell function is unequivocally documented both in vitro and in vivo [4], its role in the modulation of Tregs remains unresolved. Tregs are a subset of T cells with a critical role in the maintenance of tolerance and immune homeostasis due to their ability to suppress the immune responses [5]. Based on cell surface markers or cytokine secretion profi les, Tregs can be grouped into two categories: natural Tregs (nTregs) and induced Tregs (iTregs). Th e natural CD4 Tregs (nTregs) are of thymic origin with an immunophenotype consisting of CD25, FOXP3, CTLA-4, LAG3 and GITR. Th ese cells suppress innate and adaptive immune cells. Conventional T cells in the presence of exogenous transforming growth factor- β (TGF- β ) are transformed into iTregs and acquire immunosuppressive properties. Expression and secretion of TGF- β and interleukin-10 (IL-10) are substantially increased in iTregs. Th e exact mechanism of the immunosuppressive function of Tregs is not known. It is proposed that in cancer, Tregs suppress immune responses and induce immune tolerance through multiple mechanisms, including cell contact-dependent and -independent mechanisms. Also progressive immune failure is associated with an increasing percentage of Tregs in cancer. Th us, a therapeutic regimen that includes depletion of Tregs is being tested in cancer therapy and, in particular, immunotherapy. Conversely, the eff ect of immunotherapy on the fate of Tregs is also being debated. Lenalidomide was shown to inhibit the proliferation and function of Tregs in vitro [6]. Idler et al . studied the changes in Treg population in patients with chronic lymphocytic leukemia (CLL) treated with lenalidomide over a prolonged period of time, and showed that lenalidomide decreased the percentage as well as the absolute number of Tregs [7]. However, a recent report showed that lenalidomide has a biphasic eff ect on Tregs in CLL. Treatment with lenalidomide for three cycles (28 days) increased the Tregs (percentage and absolute number), whereas a prolonged treatment for 15 cycles with progressively increasing doses of lenalidomide (increased by 5 mg/day after every two cycles of 28 days each) brought the numbers to a lower level, equivalent to that of healthy donors [8]. Lenalidomide is highly eff ective in treating newly diagnosed as well as relapsed/refractory multiple myeloma (MM) and is now being evaluated as maintenance therapy, as preventive therapy, and in combination with other new agents. In particular, the combination of dexamethasone, an immunosuppressant, and lenalidomide resulted in an impressive and long-lasting remission in patients with relapsed and/ or refractory MM [9]. Th e reason for this paradoxical but remarkable clinical response is not known. Clinical data indicate that lenalidomide in combination with dexamethasone is highly eff ective in relapsed/refractory MM following allogeneic stem cell transplant, which is associated with an increase in the number of Tregs [10]. Consistent with these