Monocytes enhance cell proliferation and LMP1 expression of nasal natural killer/T‐cell lymphoma cells by cell contact‐dependent interaction through membrane‐bound IL‐15

Abstract

Nasal natural killer (NK)/T-cell lymphoma (NNKTL) is an Epstein-Barr virus (EBV)-related malignancy with poor prognosis and has distinct histological features characterized by angiocentric and polymorphous lymphoreticular infiltrates including inflammatory cells such as granulocytes, monocytes, macrophages and lymphocytes. Here, we show that the monocytes enhance proliferation as well as LMP1 expression of NNKTL cells by cell contact-dependent interaction through membranebound interleukin (IL)-15. We used two EBV-positive NK-cell lines, SNK6 and KAI3, which originated from two patients-SNK6 from a patient with NNKTL and KAI3 from a patient with a severe mosquito allergy. We cocultured the cell lines with granulocytes or monocytes and examined whether proliferation, survival and LMP1 expression of the cells changed. Although cocultured granulocytes did not affect proliferation, survival or LMP1 expression of the cells, cocultured monocytes enhanced both proliferation and LMP1 expression in a dose-dependent manner. These phenomena were not seen when monocytes were placed in a separate chamber. Moreover, the monocyte-inducible proliferation and LMP1 expression were inhibited by treatment with an antibody against IL-15. Furthermore, production of interferon-gamma-inducible protein (IP)-10 were enhanced by coculture with monocytes and were inhibited by the antibody. Immunohistological studies confirmed that a number of infiltrating CD14-positive monocytes contacted CD56-positive lymphoma cells in all of 20 NNKTL tissues tested. These results suggest that monocytes enhance cell growth as well as LMP1 expression of NNKTL cells by cell contactdependent interaction through membrane-bound IL-15. In the microenvironment of NNKTL tissue, a positive feedback loop of interaction between lymphoma cells and monocytes may be present and contribute to lymphoma progression.

Serum CD163 and TARC as Disease Response Biomarkers in Classical Hodgkin Lymphoma

“…Intriguingly, we show a strong positive correlation with sCD163 and plasma EBV-DNA levels, suggesting a possible interaction with EBV proteins in HRS cells and CD163 þ monocyte/ macrophages. Monocytes have been shown to enhance proliferation and LMP1 expression of tumor cells in nasal natural killer/T-cell lymphoma (NNKTL), which is also an EBV latency type II-associated malignancy (39). Consistent with this, 4 studies (with sample sizes ranging from approximately 100-300 tissues) have found that tissue CD163 protein does correlate with the presence of EBV-positive HRS cells (13)(14)(15)(16).…”

Novel Targets for Natural Killer/T-cell Lymphoma Immunotherapy

“…Our group has demonstrated that monocytes but not granulocytes contribute to NKTL proliferation in a membrane-bound IL-15-dependent manner [21]. Monocytes co-localized with lymphoma cells in NKTL clinical samples.…”

Soluble ICAM-1 secretion and its functional role as an autocrine growth factor in nasal NK/T cell lymphoma cells

“…We have previously shown that SNK6 cells produce several cytokines and chemokines such as interferon (IFN)-γ, interleukin (IL)-9, IL-10 and interferon-γ-inducible protein (IP)-10, which play roles in cellular proliferation and invasion in an autocrine manner [7][8][9]. Furthermore, monocytes attracted by IP-10 enhance the proliferation via cell-to-cell contact [10]. However, the biological characteristics of NNKTL are yet to be completely understood.…”