Multiple Immunological Aspects in Myeloma

Multiple myeloma (MM) is the second most common hematological malignancy, characterized by clonal proliferation of neoplastic plasma cells in the bone marrow, causing hematopoietic suppression and impaired antibody production. Bacterial infections remains a major cause of mortality in MM. As in in most malignancies, myeloma cells modify their microenvironment to promote tumor growth, including suppression of the immune system.This thesis investigated different aspects of neutrophil function, including the immunoregulatory role of normal density granulocytes (NDGs) and myeloid-derived suppressor cells (MDSCs).In paper I, neutrophils from patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed MM exhibited reduced phagocytic ability and capacity of oxidative burst compared with healthy controls. The impairment was most pronounced in bone marrow (BM) samples and might contribute to the increased susceptibility to bacterial infections in MM. Lenalidomide treatment was associated with restored neutrophil function.In paper II, levels and suppressive abilities of MDSCs as well as NDGs, were investigated. No increase in MDSC levels was detected in peripheral blood (PB) or BM, and they exhibited limited suppressive ability toward T cells, suggesting that MDSCs are not major contributors to MM pathogenesis. NDGs, however, displayed immunoregulatory activity, potentially contributing to MM development.In paper III, NDGs induced a contact-dependent suppression of T cell proliferation, mediated by CD11b and reactive oxygen species (ROS) produced by NDGs. NDGs also induced a loss of the T helper (Th)1 surface marker CD183, which was unrelated to ligand binding. Moreover, incubation with NDGs suppressed cytokine production by Th1, Th2 and Th17 cells.In paper IV, we tested whether NDGs from PB or BM of MM patients exerted suppressive effects on Tcells, similar to MDSCs. NDGs from the BM of MM patients, but not healthy donors, inhibited T cell proliferation. This effect could not be explained by alterations in maturity levels of NDGs in the bone marrow. NDGs in PB from both MM patients and controls inhibited T cell proliferation and IFN-γ production. PB NDGs did not need to be preactivated to mediate suppressive effects. Instead, they became activated during coculture, indicating that contact with activated T cells is important for their regulatory function. The inhibitory effect was ROS dependent and reversed with the inhibitor catalase. This suggests that NDGs possesses MDSC-like properties that might support myeloma cell growth.