Increased Immune Suppressive CD14⁺ hla-DR^neg Circulating Monocytes Are Found in Aggressive Non-Hodgkin's Lymphoma and Correlated with Increased Arginase I Level.

Abstract 970

Despite advances in treatments for patients with non-Hodgkin's lymphoma (NHL), the relapse rates remain high and 40% of diffuse large B-cell NHL (DLBCL) patients die of disease. These patients have variable levels of immunodeficiency that may impact their prognosis. Previously we reported that monocytes in relapsed NHL patients suppress both autologous and allogeneic T cell proliferation and that these monocytes were unable to mature into dendritic cells in vitro. These suppressive functions were associated with increased frequency of CD14⁺HLA-DR^neg monocytes in NHL patients (NHL: 29.4 ± 3.2%, n = 36; healthy donors 7.54 ± 0.97%, n = 27; p < 0.0001). This phenotype is distinct from other myeloid suppressors (Lin⁻CD33⁺HLA-DR⁻) or non-classical monocytes (CD16+), neither of which was different in numbers between NHL and healthy donors. We have now expanded our study cohort and found that the percentage of CD14⁺HLA-DR^neg cells among circulating monocytes was increased in patients with more aggressive disease: DLBCL 37.5 ± 5.11%, n = 16 vs SLL and MALT lymphoma 15.8 ± 4.02%, n = 7; p = 0.01. Two newly diagnosed patients and three patients with localized disease amenable to resection all had frequencies of CD14⁺HLA-DR^neg monocytes closer to that of healthy donors whereas 5 of the 6 patients with low grade NHL that transformed to DLBCL had significantly elevated percentage of these suppressive monocytes (49.1 ± 4.70%). To better understand the mechanism of immune suppression by CD14⁺HLA-DR^neg monocytes, we investigated production of IFN-alpha induced by CpG oligodeoxynucleotide. Monocytes from NHL patients were less effective at IFN-alpha production (0.54 ± 0.22%, n = 4) compared to healthy donors (1.37 ± 0.25%, n = 4; p = 0.04). The corresponding culture supernatants also had a 4-fold reduction in IFN-alpha level by ELISA (p = 0.01). Reduced IFN-alpha production and subsequent decreased stimulatory response may contribute to diminished treatment response to CpG in NHL. Finally, we also found that the frequency of CD14⁺HLA-DR^neg monocytes correlated with increasing plasma levels of arginase I, a known mediator of T cell suppression (n = 16, p = 0.06). Such correlation was not observed for circulating VEGF, IL-6 or IL-10. Taken together we have described a population of immunosuppressive CD14⁺HLA-DR^neg monocytes in NHL patients that is more prevalent in aggressive disease and likely suppresses T cell function through multiple mechanisms including arginine metabolism. This work was supported through the University of Iowa and Mayo Clinic Lymphoma SPORE CA097274 and the Gerstner Family Foundation.