Immunosuppressive CD14+HLA-DR(low)/- monocytes in B-cell non-Hodgkin lymphoma.
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-DR(low/-)CD120b(low)). Patients with increased ratios of CD14(+)HLA-DR(low/-) monocytes had more aggressive disease and suppressed immune functions. In summary, we report that CD14(+)HLA-DR(low/-) monocytes are a major and multifactorial contributor to systemic immunosuppression in NHL.
Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
Yi
Y
Lin
Michael P
MP
Gustafson
Peggy A
PA
Bulur
Dennis A
DA
Gastineau
Thomas E
TE
Witzig
Allan B
AB
Dietz
D001119:Arginase / Q000235:genetics / Q000378:metabolism; D001120:Arginine / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000378:metabolism*; D006801:Humans; D016130:Immunophenotyping; D007165:Immunosuppression Therapy; D016898:Interferon-alpha / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
D006684:HLA-DR Antigens; D016898:Interferon-alpha; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D050794:STAT1 Transcription Factor; D007371:Interferon-gamma; D001120:Arginine; D001119:Arginase