Multiple myeloma (MM) is a progressive B-lineage neoplasia characterized by clonal proliferation of malignant plasma cells. Increased numbers of regulatory T cells (Tregs) were determined in mouse models and in patients with MM, which correlated with disease burden. Thus, it became rational to target Tregs for treating MM. The effects of common chemotherapeutic drugs on Tregs are reviewed with a focus on cyclophosphamide (CYC). Studies indicated that selective depletion of Tregs may be accomplished following the administration of a low-dose CYC. We report that continuous nonfrequent administrations of CYC at low doses block the renewal of Tregs in MM-affected mice and enable the restoration of an efficient immune response against the tumor cells, thereby leading to prolonged survival and prevention of disease recurrence. Hence, distinctive time-schedule injections of low-dose CYC are beneficial for breaking immune tolerance against MM tumor cells. 1. Introduction Multiple myeloma (MM) is a progressive B lineage neoplasia characterized by clonal proliferation of malignant plasma cells that localize in the bone marrow (BM) replacing the normal BM population. A reduced level of polyclonal immunoglobulins is a consistent feature of active MM reflecting the suppression of CD19+ lymphocytes that correlate inversely with the disease stage. The relationship between myeloma plasma cells and the BM microenvironment is critical for the maintenance of the disease. Tumor cells and stromal cells interact via adhesion molecules and cytokine networks to simultaneously promote progression of the disease leading to bone destruction, vertebral collapse, hypercalcemia, renal failure, hypogammaglobulinemia, and peripheral neuropathy. The disease is associated with both cellular and humoral immune deficiencies [1]. Recent studies have revealed that CD4+CD25highFoxp3+ regulatory T cells (Tregs), which are physiologically engaged in the maintenance of immunological self-tolerance, play critical roles for the control of antitumor immune responses. Increased numbers of Tregs were documented in peripheral blood, tumor mass, and draining lymph nodes from patients of a wide spectrum of cancers. A strong correlation exists between Treg levels and the progression of cancer. The increased number of Tregs was reported to reflect poor prognosis [2] and is associated with suppression of T cell proliferation, downregulation of proinflammatory cytokines, and involvement in tumor tolerance to self antigens. Thus, new anticancer strategies involving interference in Treg biology by means of
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