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 6

CD84 expression is regulated in a MIF-dependent manner in the MM microenvironment.

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CD84 expression is regulated in a MIF-dependent manner in the MM microen...
(A and B) PB CD14+ cells derived from healthy volunteers were cultured alone or with the human myeloma cell lines (MM.1S, U266, KMS11) at a ratio of 1:2. After 48 hours, the CD14+ cells were analyzed by flow cytometry for CD84 (A) and PD-L1 (B) expression (n = 3). Representative histograms are shown. (C) MIF protein expression was analyzed in the human MM cell lines NCI-H929, MM.1S, U266, RPMI-8226, L363, MM.1R, and Raji cell line (positive control) by Western blot analysis. (D and E) PB CD14+ cells from healthy donors (D) or THP1 cells (E) were cultured with or without 200 ng/mL human recombinant MIF (hrMIF). After 48 hours, the cells were analyzed for CD84 and PD-L1 expression by flow cytometry (n = 3). (F and G) BM from C57BL/KaLwRij WT mice (F) or 5TGM1-injected C57BL/KaLwRij mice (G) was grown until an almost confluent adherent cell layer was formed. Thereafter, 100 ng/mL MIF was added. After 48 hours, the cells were harvested and analyzed by flow cytometry (excluding CD45+ and CD138+ cells) for CD84 expression (n = 3–5). (H and I) MM.1S cells were transfected using MIF or control siRNA (10 μM/mL). After 48 hours, the medium was replaced with fresh culture medium, and cells were grown an additional 72 hours for collection of supernatant. After 72 hours, the supernatants of the cells were transferred to PB CD14+ cells derived from healthy donors. After 48 hours, the CD14+ cells were harvested and analyzed by flow cytometry for CD84 (H) and PD-L1 (I) expression (n = 5).