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 4

CD84 upregulates PD-L1 expression in MDSCs.

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CD84 upregulates PD-L1 expression in MDSCs. (A and B) Sorted primary M-M...
(A and B) Sorted primary M-MDSCs (CD14+, CD15–, CD11b+, HLA-DR–) (A) and G-MDSCs (CD15+, CD14–, CD11b+, HLA-DR–) (B) from BM aspirates of MM samples were analyzed for PD-L1 message by qPCR. (C–F) Sorted (mRNA) or whole BM (protein) primary M-MDSCs (LY6C+, LY6G–, CD11b+, CD11C–) (C and E), and G-MDSCs (LY6G+, LY6Clo, CD11b+, CD11C–) (D and F) from BM aspirates taken from 5TGM1-injected mice were incubated in the presence of anti-CD84 (B4) blocking or isotype control antibodies and analyzed for PD-L1 mRNA (C and D) and protein (E and F) by qPCR or FACS analysis, respectively (n = 4). Representative histograms are shown in E and F. (G and H) Sorted M-MDSCs (G) and G-MDSCs (H) were treated with anti-CD84 B4 inhibitory or control antibody and cocultured for 72 hours with WT whole spleens at a ratio of 1:4, and the percentage of dividing CD8+ T cells and IFN-γ was analyzed thereafter (n = 4–7, *P < 0.05). (I) LentiCRISPR-v2 CRISPR/Cas9 system was established in the THP1 cell line with constitutive KO of CD84 expression, and protein levels of CD84 and PD-L1 were determined by flow cytometry (n = 3). (J) THP1 cells were activated with anti-CD84 or control antibodies, and CD84, p-mTOR, pAKT, pS6, and PD-L1 expression levels were determined by Western blotting analysis. *P < 0.05, **P < 0.01 with either 1-tailed (B, F, E, and G) or 2-tailed unpaired or paired 2-tailed t test for pairwise comparisons.