Abstract
Background: Plasmacytoid dendritic cells (pDCs) play prominent roles in mediating innate and adaptive immune responses. However, it is unclear how pDCs contribute to the immunosuppressive tumor microenvironment described in multiple myeloma (MM). Methods: Newly diagnosed myeloma patients (MM, n = 37) were analyzed to determine the pDC counts in comparison to peripheral blood (PB, n = 53) and bone marrow (BM, n = 10) samples of age-matched healthy donors (HD) using flow cytometry. Second, proliferation of myeloma tumor cells in the presence of freshly isolated pDCs was examined. Third, production of IFNα by pDCs co-cultured with MM cells was determined by intracellular staining. Results: We found a highly significant reduction of circulating pDCs (p < 0.0001) and in bone marrow (p < 0.0001) of MM patients compared to HD. We also observed a significant decrease of pDCs (p = 0.004) in BM in patients with monoclonal gammopathy of undetermined significance (MGUS, n = 12). Importantly, we determined that pDCs promote proliferation specifically of MM cells and not the stromal cells and that pDCs secrete IFNα upon co-culture with MM tumor cells. Conclusions: Our results show altered pDC frequencies in the BM microenvironment in MGUS and MM patients at diagnosis. We showed the tumor-promoting function of pDCs that may mediate immune deficiencies affecting long-term disease control and treatment outcome.
Highlights
Plasmacytoid dendritic cells are a distinct lineage of bone marrow-derived cells that reside mainly in blood and lymphoid organs but can be found in sites of infection and inflammation
Our results show significant reduction of Plasmacytoid dendritic cells (pDCs) in peripheral blood and bone marrow of MM patients compared to healthy donors (HD)
Plasmacytoid Dendritic Cells in Myeloma Patients Compared to Healthy Donors
Summary
Plasmacytoid dendritic cells (pDCs) are a distinct lineage of bone marrow-derived cells that reside mainly in blood and lymphoid organs but can be found in sites of infection and inflammation. They express pathogen recognition receptors TLR-7 and TLR-9 mainly residing in the endosomes responding to viral RNA and DNA upon cell infection. Multiple myeloma (MM) is characterized by the clonal expansion and accumulation of malignant plasma cells in the bone marrow, producing high amounts of monoclonal immunoglobulin [18,19]. It is considered the second most common blood cancer and remains incurable due to the development of cancer cell intrinsic mechanisms [20,21]. These findings confirm aberrant roles of pDCs within the BM tumor microenvironment in myeloma
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