Levels of sIL-2R in Sera Depend On Number of CD25-Positive Lymphoma Cells and MMP-9-Positive Macrophages in DLBCL.

Abstract 2927

Poster Board II-903

We investigated the significance of serum soluble IL-2R (sIL-2R) in diffuse large B-cell (DLBCL) and follicular lymphoma (FL) compared to that in adult T cell leukemia (ATL). In ATL, levels of sIL-2R may depend on tumor burden expressing IL-2R (CD25) and producing matrix metalloproteinase-9 (MMP-9), as MMP-9 cleaves the αa-chain of IL-2R. First, we confirmed that MMP-9 cleaves IL-2R, as CD25 expression was decreased on the cell surface after treatment with rMMP-9, and sIL-2R was decreased in the supernatant by down-regulation via MMP-9 shRNA and MMP-9 inhibitor in the ATL cell line MT1. We then measured serum sIL-2R and plasma MMP-9 (pMMP-9) in lymphoma patients, and analyzed CD25 expression by flow cytometry and MMP-9 expression by immunohistochemistry (IHC) in biopsy samples. Gelatin-zymography was also performed in order to detect MMP-9 activity in representative ML patients with DLBCL and FL using the supernatant of purified CD19-positive cells. MMP-9 expression was detected in neoplastic cells by IHC in some ATL patients; however, MMP-9-positive cells were macrophages in DLBCL and FL. Contrary to our expectation that lymphoma cells in intravascular lymphoma (IVL) express MMP-9 strongly because MMP-9 is an important factor in blood vessel invasion, MMP-9 expression was not also detected in lymphoma cells in IVL. Interestingly, gelatin-zymography revealed MMP-9 activity in the supernatant of purified CD19-positive cells of DLBCL and FL. Therefore, IHC may not detect MMP-9 expression in paraffin sections unless lymphoma cells express MMP-9 strongly. In addition, there was no correlation between sIL-2R and pMMP-9 levels. The number of MMP-9-positive macrophages (MPMs) was higher in DLBCL than in FL, and MPMs were correlated with pMMP-9 levels in DLBCL, particularly in cases with high sIL-2R levels. On the other hand, this relationship was not significant in FL. Therefore, the main source of sIL-2R was thought to be T cells near lymphoma cells and macrophages, as lymphoma cells expressed CD25 partially in some DLBCL and FL cases. Taken together, our data indicate that sIL-2R levels are correlated with lymphoma cells expressing CD25 and the number of MPMs in DLBCL. Considering our previous data showing that levels of sIL-2R are correlated with prognosis in DLBCL, CD25 expression in lymphoma cells in DLBCL may be a prognostic marker and the number of MPMs may be correlated with the level of disease activity.