Significance of Serum Soluble IL-2R in DLBCL and FL Is Different from That in ATL
Authors: Yoshida Noriaki , Sakai Akira , Okikawa Yoshiko , Nitta Hideaki , Nishisaka Takashi , Kimura Akiro 
Published: April 2020

Abstract
Interleukin-2 receptor (IL2R) is usually expressed on activated T cells by antigen stimulation and on pre-B cells during B cell differentiation. Soluble IL-2R (sIL-2R) in serum is a truncated form of the 55-kDa chain of IL-2R, which is believed to be produced by cleavage by proteases. The concentration of sIL-2R in serum has been an index of tumor burden in adult T cell leukemia/lymphoma (ATL), in which CD4-positive T cells express IL-2R (CD25) on the cell surface. Subsequently, analysis of serum sIL-2R concentration has also been useful in predicting disease activity and response to treatment in B cell lymphoma. However, it is still unclear whether B cell lymphoma cells express IL-2R (CD25) or whether serum sIL-2R concentration is due to IL-2R on B cell lymphoma cells. Furthermore, it is unclear how sIL-2R is released from IL-2R in ATL. First, we examined whether serum sIL-2R concentration is a prognostic factor in previously untreated patients with DLBCL (n = 105, median age 67.0 (18–91 years)) or FL (n = 30, median age 60.0 (40–82 years)) diagnosed between January 2001 and December 2005, and who received six cycles of R + CHOP or R + THP-COP therapy. Patients who relapsed or had disease progression after R + CHOP or R + THP-COP received R + EDAP or R + ICE for DLBCL, and R + FND for FL. The 5-year OS rates for patients with sIL-2R levels of &lt; 1500 U/ml and ⊠ 1500 U/ml were 76% and 62%, respectively (p &lt; 0.05) in DLBCL, and 100% and 79.3%, respectively (p = 0.19) in FL. Next, we analyzed IL-2R (CD25) expression on lymphoma cells by flow cytometry. Nine of 25 patients with DLBCL and 4 of 11 patients with FL showed CD25 expression. Some T cells (CD3-positive cells) expressed CD25 in both lymphomas. On the other hand, 7 of 7 patients with MCL expressed CD25. There was no significant relationship between serum sIL-2R concentrations and CD25 expression on lymphoma cells or clinical stage in either DLBCL or FL. Metalloproteinase-9 (MMP-9) is reported to be an important protease for releasing sIL-2R from IL-2R. However, there was no significant relationship between MMP-9 and sIL-2R levels in sera from patients with DLBCL or FL. On the other hand, 7 of 7 patients with ATL showed high concentration of MMP-9 (&gt; 128 ng/ml) irrespective of sIL-2R levels. We then confirmed MMP-9 expression in 3 ATL cell lines by Western blotting, and addition of MMP-9 inhibitor to culture media of these cell lines significantly decreased sIL-2R levels in supernatants. On immunohistochemical staining (IHC) using anti-MMP-9 antibody, macrophages not lymphoma cells or T cells were positive for MMP-9 in DLBCL and FL. These findings suggest that high serum sIL-2R concentrations in ATL are due to the cleavage of IL-2R by MMP-9 produced by ATL cells. On the other hand, the main source of sIL-2R may be due to release from activated T cells in DLBCL and FL. Therefore, serum sIL-2R levels may indicate activity of neoplastic cells in ATL; however, its levels may reflex the activity of microenviromental non-neoplastic cells in DLBCL and FL.