In this paper, Chauhan and colleagues from Dana-Farber Cancer Center used both in vitro models of multiple myeloma (MM) cells and in vivo murine xenograft models of human MM to define the role of plasmacytoid dendritic cells (pDCs) in the pathogenesis of MM. Immunohistochemical and phenotypic analysis demonstrates more frequent pDCs in MM patients than normal bone marrow (BM) and more pDCs in patient BM than peripheral blood (PB).
Importantly, patient pDCs are functionally distinct from normal pDCs in two major aspects. First, patient pDCs have decreased ability to stimulate allogeneic and autologous T-cell proliferation compared to normal pDCs, suggesting that they may contribute, at least in part, to the immune deficiency characteristic of MM. Second, patient pDCs trigger proliferation of cells from MM cell lines and patients to a greater extent than do bone marrow stromal cells (BMSCs), and this is associated with phosphorylation of the intracellular signaling molecule ERK and with prolonged tumor cell survival. This effect appears to be both cell-cell contact and cytokine-mediated, since this effect is triggered by both non-irradiated and irradiated pDCs and occurs even in Transwell insert systems in which MM cells are proximate to pDCs, but pDC-MM cell contact is precluded. No similar effects are observed in normal plasma cells. Importantly, pDCs also confer resistance to conventional (dexamethasone) and novel (bortezomib, lenalidomide) MM therapies. This effect is associated with up-regulation of chymotrypsin-like, caspase-like, and trypsin-like proteasome activities. Moreover, pDCs induced up-regulation of NF-κB activity and growth in tumor cells as well as secretion of chemotactic factors, implicating their role in migration and homing of pDCs to BM, which can be blocked by an inhibitory antibody to the chemokine SDF-1α or by targeting the CXCR4-CXCL12 chemokine system with AMD3100. Similarly, MM cell growth triggered by pDCs can be abrogated by blockade of BAFF, a tumor necrosis factor family member. In vivo injection of pDCs with MM cells in murine xenograft models augments tumor cell growth and associated angiogenesis, confirming sequelae delineated in vitro. Finally, the use of CpGs to induce maturation of pDCs both restores their effector cell stimulatory capacity and attenuates their ability to promote MM cell growth.
In Brief
In the past five years, bortezomib, thalidomide, lenalidomide, and bortezomib/pegylated doxorubicin have been approved in Europe and the United States to treat MM. All have been shown to induce cytotoxicity against MM cells in the BM — both in vitro and in vivo using xenograft models of human MM. All were first shown to be efficacious in relapsed refractory MM, then relapsed MM, and most recently all of these drugs have moved to first-line therapy for newly diagnosed patients with MM. As a direct consequence, median survival of affected patients has doubled from three to four years to seven years. Although first experiments demonstrating cell adhesion-mediated drug resistance (CAM-DR) to conventional therapies utilized MM cells binding to extracellular matrix proteins, subsequent studies of adhesion of MM cells to BMSCs have similarly defined the importance of accessory cells and of cytokines promoting tumor cell growth, survival, and drug resistance. Therefore, interactions of multiple accessory cell types (osteoclasts, osteoblasts, endothelial cells, BMSCs, and DCs) with MM cells, as well as the resultant direct (activation of growth, survival, and resistance signaling in MM cells) and indirect (induction of chemokines and cytokines) biologic sequelae, now markedly expand the spectrum of potential novel therapeutic targets. Importantly, novel therapies directed at these interactions offer the potential to affect both tumor and host factors (i.e., immunity) and thereby improve patient outcome.
