Immune Functions of Signaling Lymphocytic Activation Molecule Family Molecules in Multiple Myeloma.

Mariko Ishibashi,Rimpei Morita,Hideto Tamura

doi:10.3390/cancers13020279

Abstract

Simple SummaryMultiple myeloma (MM) is an incurable hematological malignancy characterized by an increase in abnormal plasma cells. Disease progression, drug resistance, and immunosuppression in MM are associated with immune-related molecules, such as immune checkpoint and co-stimulatory molecules, present in the tumor microenvironment. Novel agents targeting these cell-surface molecules are currently under development, including monoclonal antibodies, bispecific monoclonal antibodies, and chimera antigen receptor T-cell therapies. In this review, we focus on the signaling lymphocytic activation molecule family receptors and provide an overview of their biological functions and novel therapies in MM.The signaling lymphocytic activation molecule (SLAM) family receptors are expressed on various immune cells and malignant plasma cells in multiple myeloma (MM) patients. In immune cells, most SLAM family molecules bind to themselves to transmit co-stimulatory signals through the recruiting adaptor proteins SLAM-associated protein (SAP) or Ewing’s sarcoma-associated transcript 2 (EAT-2), which target immunoreceptor tyrosine-based switch motifs in the cytoplasmic regions of the receptors. Notably, SLAMF2, SLAMF3, SLAMF6, and SLAMF7 are strongly and constitutively expressed on MM cells that do not express the adaptor proteins SAP and EAT-2. This review summarizes recent studies on the expression and biological functions of SLAM family receptors during the malignant progression of MM and the resulting preclinical and clinical research involving four SLAM family receptors. A better understanding of the relationship between SLAM family receptors and MM disease progression may lead to the development of novel immunotherapies for relapse prevention.

Highlights

Multiple myeloma (MM) is a B-cell malignancy that arises from the clonal expansion of aberrant plasma cells (MM cells)
Several molecules have been selected as candidate targets for MM immunotherapies, including signaling lymphocytic activation molecule (SLAM) family 7 (SLAMF7) and CD38, which are targeted by elotuzumab and daratumumab/isatuximab, respectively, and other cell-surface antigens such as B-cell maturation antigen (BCMA), CD56, CD138, CD74, interleukin (IL)-6 receptor, vascular endothelial growth factor (VEGF), and activated conformation of integrin β7 [11,12,13]
The SLAM family receptors SLAMF2, SLAMF3, SLAMF6, and SLAMF7 are strongly expressed on MM cells, and SLAMF3 and SLAMF7 play crucial roles in MM pathogenesis

Summary

Introduction

Multiple myeloma (MM) is a B-cell malignancy that arises from the clonal expansion of aberrant plasma cells (MM cells). In addition to the accumulation of clonal plasma cells, MM is characterized by elevated levels of monoclonal protein (M-protein), renal failure, hypercalcemia, anemia, and bone lesions [1,2]. This malignancy is caused by multiple genetic alterations and microenvironmental changes in bone marrow (BM) cells and nearly always develops from monoclonal gammopathy of undetermined significance (MGUS), a precancerous condition [1,3,4,5]. Many clinical trials of immunotherapies for MM are ongoing, with a particular focus on IMiDs, monoclonal antibodies, bispecific antibodies, immune checkpoint inhibitors, and chimeric antigen receptor (CAR) T-cell therapy. An understanding of the expression and biological functions of these molecules in MM is important to support the development of novel therapeutic targets and the prevention of treatment-related side effects

Overview of SLAM Family Receptors

Findings

Conclusions