Optimizing immunotherapy in multiple myeloma: Restoring the function of patients' monocyte-derived dendritic cells by inhibiting p38 or activating MEK/ERK MAPK and neutralizing interleukin-6 in progenitor cells.
Previous studies demonstrated that circulating dendritic cells (DCs) in myeloma patients were functionally abnormal. However, the phenotype and function of patients' monocyte-derived DCs (MoDCs), which are commonly used for immunotherapy, were poorly defined. This study was undertaken to examine the quality of MoDCs from myeloma patients compared with cells from healthy donors. We found that patient-derived MoDCs are phenotypically and functionally defective. Compared with their normal counterparts, patient-derived, mature MoDCs expressed significantly lower levels of CD1a, CD40, CD80, and HLA-DR and were poor at activating alloreactive T cells, presenting recall antigen, and activating autologous antigen- and myeloma-specific T cells. These abnormalities may be attributed to elevated production of autocrine cytokines such as IL-6, activated p38 and STAT3, and inhibited MEK/ERK signaling pathways in the progenitor cells. Treatment with neutralizing IL-6-specific antibody and, more importantly, p38 inhibitor, or both, could correct these abnormalities. Treating patient-derived cells with these agents not only significantly increased cell yield but also produced MoDCs that were as functional as their normal counterparts. Thus, this study has delineated the mechanistic defects of MoDCs from myeloma patients and identified ways for restoring the function of the cells to improve the efficacy of DC-based immunotherapy in this disease.
Wang
Siqing
S
Department of Lymphoma and Myeloma, Center for Cancer Immunology Research, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Hong
Sungyoul
S
Yang
Jing
J
Qian
Jianfei
J
Zhang
Xiang
X
Shpall
Elizabeth
E
Kwak
Larry W
LW
Yi
Qing
Q
D000906:Antibodies / Q000494:pharmacology* / Q000627:therapeutic use; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D015850:Interleukin-6 / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000276:immunology*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*; D009000:Monocytes / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D009101:Multiple Myeloma / Q000201:enzymology / Q000276:immunology / Q000473:pathology / Q000628:therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000276:immunology*; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D020127:Recovery of Function / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D000093242:Interleukin-6 Inhibitors
D000906:Antibodies; D015703:Antigens, CD; D006684:HLA-DR Antigens; D015850:Interleukin-6; D020928:Mitogen-Activated Protein Kinases; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D000093242:Interleukin-6 Inhibitors