Immunosuppressive CD14+HLA-DRlow/− monocytes in B-cell non-Hodgkin lymphoma

• Published in: Blood Vol. 117; no. 3; pp. 872 - 881
• Main Authors: Lin, Yi, Gustafson, Michael P., Bulur, Peggy A., Gastineau, Dennis A., Witzig, Thomas E., Dietz, Allan B.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 20.01.2011; Americain Society of Hematology; American Society of Hematology
• Series: Lymphoid Neoplasia
• Subjects: alpha -Interferon; Arginase; Arginine; Biological and medical sciences; Cell proliferation; CpG islands; Dendritic cells; Differentiation; gamma -Interferon; Hematologic and hematopoietic diseases; Histocompatibility antigen HLA; Immune response; Immunoregulation; Immunosuppression; Interleukin 10; Interleukin 6; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocytes B; Lymphocytes T; Lymphoid Neoplasia; Lymphoma; Medical sciences; Metabolism; Monocytes; Peripheral blood mononuclear cells; Phosphorylation; Risk factors; Stat1 protein; Supplementation; Tumor necrosis factor- alpha; Immunosuppression; Hematology; Monocyte; Lymphoproliferative syndrome; Malignant hemopathy; B-Lymphocyte; Immunosuppressive agent; Non Hodgkin lymphoma; Cancer
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-05-283820

Immunosuppression is a known risk factor for B-cell non-Hodgkin lymphoma (NHL), yet mechanisms of tumor-associated immunosuppression remain to be fully characterized. We examined the immunophenotype of 40 NHL patients and 27 age-matched healthy volunteers to better understand systemic immune suppression. NHL peripheral blood mononuclear cells had significantly decreased interferon-γ production and proliferation. This suppression was not the result of regulatory T cells, interleukin-6 or interleukin-10, as these factors were not different between NHL and healthy volunteers (controls). We were able to restore T-cell proliferation by removing NHL monocytes, suggesting that these monocytes are suppressive. This suppression was mediated in part through arginine metabolism as exogenous arginine supplementation partially overcame monocytes' suppression of T-cell proliferation in vitro and NHL patients had elevated arginase I in their plasma. NHL monocytes had impaired STAT1 phosphorylation and interferon-α production to CpG stimulation and a dendritic cell differentiation deficiency. Further studies demonstrated that monocytes from NHL patients had decreased HLA-DR and Tumor necrosis factor-α receptor II (CD120b) expression compared with controls (CD14+HLA-DRlow/−CD120blow). Patients with increased ratios of CD14+HLA-DRlow/− monocytes had more aggressive disease and suppressed immune functions. In summary, we report that CD14+HLA-DRlow/− monocytes are a major and multifactorial contributor to systemic immunosuppression in NHL.