CD84 is a regulator of the immunosuppressive microenvironment in multiple myeloma
Hadas Lewinsky, … , Steven Rosen, Idit Shachar
Hadas Lewinsky, … , Steven Rosen, Idit Shachar
Published January 19, 2021
Citation Information: JCI Insight. 2021;6(4):e141683. https://doi.org/10.1172/jci.insight.141683.
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Research Article Hematology Oncology

CD84 is a regulator of the immunosuppressive microenvironment in multiple myeloma

Abstract

Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) within the BM. The BM microenvironment supports survival of the malignant cells and is composed of cellular fractions that foster myeloma development and progression by suppression of the immune response. Despite major progress in understanding the biology and pathophysiology of MM, this disease is still incurable and requires aggressive treatment with significant side effects. CD84 is a self-binding immunoreceptor belonging to the signaling lymphocyte activation molecule (SLAM) family. Previously, we showed that CD84 bridges between chronic lymphocytic leukemia cells and their microenvironment, and it regulates T cell function. In the current study, we investigated the role of CD84 in MM. Our results show that MM cells express low levels of CD84. However, these cells secrete the cytokine macrophage migration inhibitory factor (MIF), which induces CD84 expression on cells in their microenvironment. Its activation leads to an elevation of expression of genes regulating differentiation to monocytic/granulocytic–myeloid-derived suppressor cells (M-MDSCs and G-MDSCs, respectively) and upregulation of PD-L1 expression on MDSCs, which together suppress T cell function. Downregulation of CD84 or its blocking reduce MDSC accumulation, resulting in elevated T cell activity and reduced tumor load. Our data suggest that CD84 might serve as a novel therapeutic target in MM.

Authors

Hadas Lewinsky, Emine G. Gunes, Keren David, Lihi Radomir, Matthias P. Kramer, Bianca Pellegrino, Michal Perpinial, Jing Chen, Ting-fang He, Anthony G. Mansour, Kun-Yu Teng, Supriyo Bhattacharya, Enrico Caserta, Estelle Troadec, Peter Lee, Mingye Feng, Jonathan Keats, Amrita Krishnan, Michael Rosenzweig, Jianhua Yu, Michael A. Caligiuri, Yosef Cohen, Olga Shevetz, Shirly Becker-Herman, Flavia Pichiorri, Steven Rosen, Idit Shachar

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Figure 1

CD84 is expressed on immunosuppressive cells in the MM microenvironment.

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CD84 is expressed on immunosuppressive cells in the MM microenvironment....
(A) CD84 expression was analyzed by FACS on MGUS, smoldering disease, and patient-derived CD138+CD38+ MM cells from the BM. Representative histograms, with percentages of the positively stained cells, are shown (n = 3–10, P = 0.44, 1-way ANOVA). (B) CD138+ 5TGM1 cells taken from spleen and BM of 5TGM1-injected C57BL/KaLwRij WT mice. A representative histogram demonstrating the percent of CD84+ BM and spleen 5TGM1 cells, is shown (n = 7–8). (C) MM BM stroma cells from MM grown in culture. Representative histograms, showing the percent of CD84+ cells, are shown (n = 3–6). (D) Stroma derived from BM aspirates of 5TGM1-injected C57BL/KaLwRij WT or noninjected mice grown in culture. A representative histogram, with percentages of CD84+ stroma cells from injected mice is shown (n = 3–7). (E and F) CD14+ cells from MM or healthy BM aspirates (E), or MM or healthy PB (F). Representative histograms, indicating percentages of positively stained cells, are shown (n = 7–16).