CD84 is a regulator of the immunosuppressive microenvironment in multiple myeloma
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
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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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 3

CD84 upregulates PD-L1 expression in MM cells and their microenvironment.

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CD84 upregulates PD-L1 expression in MM cells and their microenvironment...
(A) Sorted primary MM cells (for mRNA analysis) or total primary BM stained to identify MM cells (for protein analysis) from patients were stimulated with anti-CD84 activating or control antibodies. PD-L1 mRNA (left graph) or protein (right graph) were determined by qPCR or FACS analysis, respectively. A representative histogram, with percent of CD84+ cells, is shown. (B) BM aspirates from primary MM patients were seeded and grown until a confluent adherent layer was formed. Thereafter, CD84 was activated with anti-CD84 or control antibodies, and RNA (left graph) and protein (right graph) expression was analyzed using qPCR and flow cytometry, respectively. A representative histogram, demonstrating the percent of CD84+ cells, is shown (n = 3–5). (C) 5TGM1 cells were activated with anti-CD84 or control antibodies. PD-L1 message was analyzed by qPCR (n = 3). (D and E) 5TGM1 cells were incubated with antagonistic anti-CD84 B4 or control antibodies. PD-L1 mRNA (D) or protein (E) were analyzed by qPCR or flow cytometry, respectively. Representative histograms are shown (n = 3). (F) 5TGM1 cells were treated with either siCTRL or siCD84; RNA was purified and analyzed by qPCR for CD84 (left graph) and PD-L1 (right graph) mRNA levels (n = 3). (G) Primary PB CD14+ cells from healthy donors were treated with anti-CD84 activating antibody or control antibodies. PD-L1 mRNA (left graph) or protein (right graph) levels were analyzed by qPCR and flow cytometry, respectively (n = 3–5).