Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug–induced apoptosis

Abstract

Multiple myeloma remains an incurable disease. One of the major problems is that myeloma cells develop drug resistance on interaction with bone marrow stromal cells. In this study, we examined the effects of macrophages (Mvarphis), a type of stromal cells, on myeloma cell survival and response to chemotherapy. We showed that Mvarphi, in particular tumor-associated Mvarphi, is a protector of myeloma cells. The protective effect was dependent on direct contact between Mvarphis and myeloma cells. Mvarphis protected both myeloma cell lines and primary myeloma cells from spontaneous and chemotherapy drug-induced apoptosis by attenuating the activation and cleavage of caspase-dependent apoptotic signaling. These findings are clinically relevant because we found that CD68+ Mvarphis heavily infiltrate the bone marrow of patients with myeloma but not the bone marrow of control patients. Thus, our results indicate that Mvarphis may contribute to myeloma cell survival and resistance to chemotherapeutic treatment in vivo.

Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma

“…4 Furthermore, these mw may protect MM cells from chemotherapy drug-induced apoptosis. 5 Remarkably, tumor-associated mw may still induce Fc-dependent anti-tumor activity, 40 supporting a role for DARA-induced phagocytosis in the BM. Another approach is the combination with drugs regulating anti-phagocytic signals.…”

“…DARA can induce tumor cell killing through a number of effector mechanisms, including the Fc-dependent effector mechanisms complement-dependent cytotoxicity (CDC) and natural killer (NK)-cell mediated antibody-dependent cellular cytotoxicity (ADCC). 12 Macrophages are known to be abundantly present in the bone marrow of MM patients, 4,5 and macrophage-mediated phagocytosis has been demonstrated to be induced by several mAbs targeting MM cells. [13][14][15] The capacity of DARA to induce macrophage-mediated phagocytosis has not been studied thus far.…”

“…Antibody-dependent phagocytosis of IgG1-opsonized pathogens as well as cancer cells occurs via binding to Fcg-receptors (FcgRs), specifically via the low-affinity receptors FcgRIIa and FcgRIIIa. 1,2 Macrophages (mw), representing professional phagocytes, are abundant in tumor stroma [3][4][5] and phagocytosis by mw might therefore be a very potent mechanism of action of therapeutic Ab in cancer treatment.…”

Downregulation of MicroRNA-152 contributes to high expression of DKK1 in multiple myeloma

“…Melphalan has been demonstrated to induce apoptosis either alone or in combination with other drugs through various canonical mechanisms. [47][48][49] Antimyeloma effect of proteasomal inhibitor bortezomib was enhanced in the presence of melphalan, and follow up clinical trials showed greater plasma cell apoptosis in MM patients. 50 Apoptosis of MM cells occurs through multiple mechanisms including down-regulation of NF-kB, intrinsic and extrinsic signaling, and inhibition of MM cell adhesion to the bone marrow stromal cells.…”

Daratumumab granted breakthrough drug status

“…Excitingly, DARA is also able to induce tumor cell killing via antibody-dependent cellular phagocytosis (ADCP) by macrophages via an additional Fc-dependent effector mechanism ( Figure 2) [43]. As macrophages infiltrate the BM and may contribute to MM cell survival and resistance to chemotherapeutic treatment [44], the addition of DARA may redirect tumor-associated macrophages and therefore overcome its protective effect.…”