Myeloma and the Microenvironment: Macrophages Are a Protector of Myeloma Cells Apoptosis Induced by Chemotherapy Drugs.

Abstract 4804

Multiple myeloma is a B-cell malignancy characterized by the proliferation of plasma cells in the bone marrow. It is the second most common hematological malignancy and is still largely incurable. One of the major problems is that myeloma cells develop drug resistance upon interaction with bone marrow stromal cells. To better understand the importance of different stromal cell components in the bone marrow microenvironment, we examined the effects of macrophages on myeloma cell survival and myeloma cell response to chemotherapy. We report here that macrophages, in particular tumor-associated macrophages obtained by culturing macrophages with myeloma cell culture supernatants, are a protector of myeloma cells. Macrophages protected both myeloma cell lines and primary myeloma cells isolated from patients from spontaneous and chemotherapy drug-induced apoptosis via attenuating the activation of caspase-dependent apoptotic signaling. The protective effect was dependent on direct contact between macrophages and myeloma cells. Although tumor-associated macrophages secreted large amounts of IL-6, which is the most important survival factor for myeloma cells, our results showed that IL-6 neutralizing antibodies fail to significantly affect the protective effects of tumor-associated macrophages. The reduced numbers of apoptotic tumor cells in the cocultures were not the result of macrophage-uptake of apoptotic cells, because macrophages with or without the ability to phagocytose apoptotic cells provide similar protection to myeloma cells against chemotherapy-induced apoptosis. These findings are clinically relevant, because we examined bone marrow biopsies of patients by immunochemical analysis and found that CD68⁺ macrophages are heavily infiltrated in the bone marrow (tumor bed) of patients with myeloma but not control patients. Thus, our results indicate that macrophages are an important component of the bone marrow stromal cells and may contribute to myeloma cell survival and resistance to chemotherapeutic treatment in vivo.