TY - JOUR
T1 - Immunosuppressive CD14+HLA-DRlow/- monocytes in B-cell non-Hodgkin lymphoma
AU - Lin, Yi
AU - Gustafson, Michael P.
AU - Bulur, Peggy A.
AU - Gastineau, Dennis A.
AU - Witzig, Thomas E.
AU - Dietz, Allan B.
PY - 2011/1/20
Y1 - 2011/1/20
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2010-05-283820
DO - 10.1182/blood-2010-05-283820
M3 - Article
C2 - 21063024
AN - SCOPUS:78751689059
SN - 0006-4971
VL - 117
SP - 872
EP - 881
JO - Blood
JF - Blood
IS - 3
ER -