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
View: Text | PDF | Corrigendum
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

×

Figure 5

Blocking CD84 induces T cell–mediated killing of human MM cells.

Options: View larger image (or click on image) Download as PowerPoint
Blocking CD84 induces T cell–mediated killing of human MM cells. (A and ...
(A and B) PB CD14+ cells (A) or T cells (B) from a healthy donor were cultured alone or with MM.1S MM cell line cells at a ratio of 1:2, in the presence or absence of the anti-CD84-inhibitory (B4) or control antibodies. After 48 hours, PD-L1 (A) or PD-1(B) cell surface levels were determined by flow cytometry (n = 3). Representative plots are shown. (C) Purified PBMCs from healthy donors were treated with IgG or B4 antibodies. After 24 hours, the cells were cocultured with GFP+ MM.1S at a ratio of 6:1 for 16 hours. The percentage of 7AAD staining on GFP+ MM.1S cells was determined by flow cytometry. Representative histograms are shown (n = 3). (D–I) Primary MM BM aspirates were treated with B4 or IgG2a antibodies. After 48 hours, the percentage of MM cells (D, left graph) and annexin V staining (D, right graph), as well as PD-L1 expression (E), were determined by flow cytometry. Representative histograms, showing the percent of annexin V+ cells or B4-treated cells, are shown (n = 4–6). (F–I) M-MDSCs (F and G), and G-MDSCs (H and I) were incubated with control or B4 antibodies. Percentage of cells (F and H) and PD-L1 expression (G and I) following treatment were determined by FACS. Representative plots or histograms are shown (n = 4–5). (J and K) The percentage of CTLA-4, LAG-3, and PD-1 on CD4+ (J) and CD8+ (K) T cells from whole MM BM aspirates treated with B4 or IgG2a control antibodies was analyzed using flow cytometry. Representative histograms are shown (n = 5–7). *P < 0.05, **P < 0.01, ****P < 0.0001, with unpaired or paired t test for pairwise comparisons.