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 9

CD84 regulates functional and immunosuppressive pathways in human MM G-MDSCs.

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CD84 regulates functional and immunosuppressive pathways in human MM G-M...
(A–C) Sorted BM G-MDSCs (CD15+, CD14–, HLA-DR–, CD11B+) were activated with anti-CD84 or -IgG1k antibodies. After 24 hours, RNA was purified and sequenced using MARS-seq. (A) Volcano plot for G-MDSC genes, with gray indicating non-DE genes and with DE-expressed genes shown either in blue, for downregulated, or in red, for upregulated. (B) Highlighted GO terms from the upregulated DE genes of G-MDSCs (MGI Mammalian Phenotype, EnrichR). (C) Heatmap depicting highlighted genes from the DE genes, with log2 CD84 activated to IgG control ratio values shown for each patient (n = 3). (D–F) Primary MM BM aspirates were treated with B4 or IgG2a antibodies. After 48 hours, G-MDSCs were analyzed for CMTM6 (n = 4) (D), BCL2A1 (n = 5) (E), and HIF1α (F) protein levels. Representative plots are shown. (G and H) Primary murine sorted G-MDSC from 5TGM1-injected mice were blocked with B4 or IgG2a antibodies. RNA was purified after 24 hours, and cells were analyzed for CMTM6 (G) and BCL2A1 (H) message and protein expression. Representative histograms are shown (n = 3-4). *P < 0.05, **P < 0.01, with paired t test for pairwise comparisons. One-tailed Student’s t test was used for G and H.