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

Hadas Lewinsky,Matthias P Kramer,Supriyo Bhattacharya,Shirly Becker-Herman,Lihi Radomir,Jonathan J Keats,Mingye Feng,Idit Shachar,Michael Rosenzweig,Enrico Caserta,Bianca Pellegrino,Jianhua Yu,Jing Chen,Flavia Pichiorri,Keren David,Michael A Caligiuri,Amrita Krishnan,Estelle Troadec,Yosef Cohen,Michal Perpinial,Emine Gulsen Gunes,Steven T Rosen ,Olga Shevetz ,Kun Yu Teng ,Anthony G Mansour ,Ting He ,Peter Lee

doi:10.1172/jci.insight.141683

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.

Highlights

Multiple myeloma (MM) is a hematological malignancy caused by an accumulation of malignant plasma cells in the BM
Analysis of CD84 expression on 5TGM1 cells derived from spleen and BM of injected mice showed significantly higher expression levels of CD84 on BM cells, compared with its expression on the malignant cells derived from the spleen (Figure 1B), suggesting that CD84 might have an important role in the BM microenvironment
The cell surface receptor CD84 mediates the interaction of chronic lymphocytic leukemia (CLL) cells with their microenvironment [18] and regulates PD-L1 expression on CLL cells and their microenvironment, resulting in the regulation of T cells in the BM [19]

Summary

Introduction

Multiple myeloma (MM) is a hematological malignancy caused by an accumulation of malignant plasma cells in the BM. Interactions between myeloma cells and other cells that are part of the tumor microenvironment foster myeloma development and progression by suppression of the immune response. It was recently shown that MDSCs mediate suppression of T cell responses through the induction of T cell anergy and Treg development in the MM microenvironment [8], rendering lymphocytes unable to control tumor infiltration and progression [9]. Previous studies have shown that CD84 regulates a potentially novel survival pathway in chronic lymphocytic leukemia (CLL) [17] It bridges between CLL and various cells in the microenvironment, mediating their interaction both in vitro and in vivo [18]. CD84 regulates PD-L1/PD-1 and exhaustion marker expression on MDSCs and T cells, respectively, resulting in the downregulation of the immune response. Our results suggest a therapeutic strategy targeting CD84 in the MM microenvironment as a promising approach to induce T cell mediated antitumor activity

Results

Discussion

Methods