Immunosuppressive CD14+HLA-DRlow/- 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-gamma 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-alpha 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-alpha receptor II (CD120b) expression compared with controls (CD14(+)HLA-DR(low/-)CD120b(low)). 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. (Blood.2011;117(3):872-881)