The contributions of the host microenvironment to the pathogenesis of multiple myeloma, including progression from the non-malignant disorder monoclonal gammopathy of undetermined significance, are poorly understood. In the present study, microarray analysis of a murine model requiring a unique host microenvironment for myeloma development identified decreased host-derived adiponectin compared with normal mice. In support, clinical analysis revealed decreased serum adiponectin concentrations in monoclonal gammopathy of undetermined significance patients who subsequently progressed to myeloma. We investigated the role of adiponectin in myeloma pathogenesis and as a treatment approach, using both mice deficient in adiponectin and pharmacologic enhancement of circulating adiponectin. Increased tumor burden and bone disease were observed in myeloma-bearing adiponectin-deficient mice, and adiponectin was found to induce myeloma cell apoptosis. The apolipoprotein peptide mimetic L-4F was used for pharmacologic enhancement of adiponectin. L-4F reduced tumor burden, increased survival of myeloma-bearing mice, and prevented myeloma bone disease. Collectively, our studies have identified a novel mechanism whereby decreased host-derived adiponectin promotes myeloma tumor growth and osteolysis. Furthermore, we have established the potential therapeutic benefit of increasing adiponectin for the treatment of myeloma and the associated bone disease. (Blood. 2011;118(22):5872-5882)
The progression of multiple myeloma, a hematologic malignancy characterized by unregulated plasma cell growth, is associated with increasing innate and adaptive immune system dysfunction, notably in the T-cell repertoire. Although treatment advances in multiple myeloma have led to deeper and more durable clinical responses, the disease remains incurable for most patients. Therapeutic strategies aimed at overcoming the immunosuppressive tumor microenvironment and activating the host immune system have recently shown promise in multiple myeloma, particularly in the relapsed and/or refractory disease setting. As the efficacy of T-cell-dependent immuno-oncology therapy is likely affected by the health of the endogenous T-cell repertoire, these therapies may also provide benefit in alternate treatment settings (e.g., precursor disease; after stem cell transplantation). This review describes T-cell-associated changes during the evolution of multiple myelo-ma and provides an overview of T-cell-dependent immunooncology approaches under investigation. Vaccine and checkpoint inhibitor interventions are being explored across the multiple myeloma disease continuum; treatment modalities that redirect patient T cells to elicit an anti-multiple myeloma response, namely, chimeric antigen receptor (CAR) T cells and bispecific antibodies [including BiTE (bispecific T-cell engager) molecules], have been primarily evaluated to date in the relapsed and/or refractory disease setting. CAR T cells and bispecific antibodies/antibody constructs directed against B-cell maturation antigen have generated excitement, with clinical data demonstrating deep responses. An increased understanding of the complex interplay between the immune system and multiple myeloma throughout the disease course will aid in maximizing the potential for T-cell-dependent immuno-oncology strategies in multiple myeloma.
The rapid progression of multiple myeloma is dependent upon cellular interactions within the bone marrow microenvironment. In vitro studies suggest that bone marrow stromal cells (BMSCs) can promote myeloma growth and survival and osteolytic bone disease. However, it is not possible to recreate all cellular aspects of the bone marrow microenvironment in an in vitro system, and the contributions of BMSCs to myeloma pathogenesis in an intact, immune competent, in vivo system are unknown. To investigate this, we utilized a murine myeloma model that replicates many features of the human disease. Co-inoculation of myeloma cells and a BMSC line isolated from myeloma-permissive mice in otherwise non-permissive mice resulted in myeloma development, associated with tumor growth within bone marrow and osteolytic bone disease. In contrast, inoculation of myeloma cells alone did not result in myeloma. BMSCs inoculated alone induced osteoblast suppression, associated with an increase in serum concentrations of the Wnt signaling inhibitor, Dkk1. Dkk1 was highly expressed in BMSCs and in myeloma-permissive bone marrow. Knockdown of Dkk1 expression in BMSCs decreased their ability to promote myeloma and the associated bone disease in mice. Collectively, our results demonstrate novel roles of BMSCs and BMSC-derived Dkk1 in the pathogenesis of multiple myeloma in vivo.
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