Abstract
Multiple myeloma (MM) is associated with both cellular and humoral immune deficiencies and, despite significant advances in treatment, remains an incurable disease. Regulatory T-cells (Tregs) represent a critical subset of CD4 T-cells, characterized by CD4 + CD25+ Forkhead box P3+ (FoxP3+) phenotype, able to control peripheral tolerance and responses to foreign and tumor antigens. Tregs are elevated in various types of cancer, including hematological malignancies; in MM, data regarding Tregs function and numbers and their correlation with survival parameters are controversial. Advances in cancer biology have shown that the tumor microenvironment plays an important role in tumor progression. In MM, the highly immunosuppressive nature of the bone marrow microenvironment has been significantly elucidated in the past decade and it is now well acknowledged that targeting only the tumor clone may not be able to cure MM. Tregs within the tumor microenvironment might play a significant role in the suppression of antitumor immune responses against cancer cells and are considered to predict poor outcome in cancer patients; nonetheless the exact prognostic significance of this cell subpopulation in malignancies is still a matter of debate. In this review, we discuss the role of Tregs as an essential cell population of the MM immune microenvironment.
Highlights
Multiple myeloma (MM) is a hematopoietic malignancy characterized by the proliferation of plasma cells within bone marrow leading to anemia, bone destruction, hypercalcemia, renal failure, and infections
In our study [103], we identified Tregs as CD4 + CD25highCD127low/dim FoxP3+ cells based on literature data according to which high expression of CD25 combined with low or negative expression of CD127 on CD4 + FoxP3+ cells characterize regulatory cells with mainly immunosuppressive properties and represent 1–2% of the total number of Tregs [53,104]
In the previously mentioned studies, MM patients had increased levels of IL-17 compared to controls; this could be related to the increased amounts of IL-6 in the bone marrow of myeloma patients with active disease which promotes the production of Th17 cells from CD4 naïve cells
Summary
Multiple myeloma (MM) is a hematopoietic malignancy characterized by the proliferation of plasma cells within bone marrow leading to anemia, bone destruction, hypercalcemia, renal failure, and infections. It accounts for ≈10% of hematological malignancies and has an overall annual incidence of 4.4 cases per 100,000 population [1]. Data regarding the impact of current antimyeloma therapies, including autologous stem cell transplantation (ASCT) and novel agents i.e., proteasome inhibitors, IMiDs and monoclonal antibodies (MoAbs) on Tregs number and function are contradictory. IMiDs and CD38 MoAbs seem to improve host-antitumor immunity, by the elimination of Tregs whereas, the combination of those drugs, can possibly lead to further enhancement of the immune response, relieving eventually the immunosuppressive bone marrow microenvironment. We discuss the role of Tregs as an essential cell population of MM immune microenvironment and their implication on myeloma therapy
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