Good Cop, Bad Cop: Profiling the Immune Landscape in Multiple Myeloma

Abstract

Multiple myeloma (MM) is a dyscrasia of plasma cells (PCs) characterized by abnormal immunoglobulin (Ig) production. The disease remains incurable due to a multitude of mutations and structural abnormalities in MM cells, coupled with a favorable microenvironment and immune suppression that eventually contribute to the development of drug resistance. The bone marrow microenvironment (BMME) is composed of a cellular component comprising stromal cells, endothelial cells, osteoclasts, osteoblasts, and immune cells, and a non-cellular component made of the extracellular matrix (ECM) and the liquid milieu, which contains cytokines, growth factors, and chemokines. The bone marrow stromal cells (BMSCs) are involved in the adhesion of MM cells, promote the growth, proliferation, invasion, and drug resistance of MM cells, and are also crucial in angiogenesis and the formation of lytic bone lesions. Classical immunophenotyping in combination with advanced immune profiling using single-cell sequencing technologies has enabled immune cell-specific gene expression analysis in MM to further elucidate the roles of specific immune cell fractions from peripheral blood and bone marrow (BM) in myelomagenesis and progression, immune evasion and exhaustion mechanisms, and development of drug resistance and relapse. The review describes the role of BMME components in MM development and ongoing clinical trials using immunotherapeutic approaches.

Keywords: hematopoiesis; immune profiling; immunotherapy; multiple myeloma; tumor microenvironment.

Figure 1

Hematopoiesis is the process by which all the blood cell types are produced through differentiation from increasingly lineage-committed precursor cells in the adult BM. Broadly, the cells can be classified as myeloid or lymphoid in origin. The myeloid lineage gives rise to thrombocytes (platelets), erythrocytes, granulocytes (mast cells, basophils, neutrophils, eosinophils), macrophages, and myeloid-derived dendritic cells (DCs). The lymphoid lineage produces T- and B-lymphocytes, natural killer (NK) cells, and lymphoid DCs.

Figure 2

Normal B-cell development and myelomagenesis. Upon BCR activation by antigenic stimulus, B-cell precursors migrate from the BM to peripheral lymph nodes to elicit a short-term immune response and the remaining cells differentiate into long-lived circulating plasma and memory cells, eventually becoming resident cells in the tissue niches. Some of the post-germinal-center B-cells carrying oncogenic mutations enter the circulation as plasmablasts and memory B-cells that migrate to the BM as pre-malignant cells to establish MGUS. Further advantageous oncogenic mutations and the favorable BMME drive malignancy and MM development after which the cells become niche-independent and re-enter the circulation, resulting in extramedullary plasmacytoma.

Figure 3

Cytogenetic abnormalities and involvement of the BMME in myeloma initiation and progression. Abnormal PCs in the BM harbor chromosomal abnormalities such as translocations and aneuploidy which could establish the precursor condition of monoclonal gammopathy of uncertain significance (MGUS). BM involvement and modification of the immune landscape by myeloma cells sets off myeloma genesis, first as smoldering MM (SMM), and with the accumulation of secondary genetic abnormalities such as CNVs and epigenetic changes as well as oncogenic driver mutations, active MM is established which eventually progresses to aggressive extramedullary plasmacytoma upon bone lysis and egress from the marrow to peripheral blood.

Figure 4

Anatomy of the BMME and niche interactions of BM-resident cells during hematopoiesis. Two major niches can be described in the bone marrow: vascular and endosteal. The vascular niche is at the core of the bone marrow comprising both arteriolar and sinusoidal vessels and is associated with LepR+ or nestin+ BMSCs and CXAR cells, macrophages, megakaryocytes, sympathetic nerve fibers, Schwann cells, endothelial cells, and adipocytes. The endosteal niche is closer to terminal bone and comprises osteolineage cells—osteoblasts and osteoclasts—involved in bone formation and recycling. Secreted growth factors, cytokines, CAMs, and ECM molecules participate in an intricate signaling network to regulate HSC quiescence and differentiation/proliferation programs. The major factors involved are CXCL-12, TGF-β, G-CSF, GM-CSF, MMPs, collagens, and integrins. Particularly, the Schwann cells and stromal cells associated with the vasculature help in the regulation of HSC migration and differentiation while cells at the endosteal surface promote HSC quiescence and maintenance of their self-renewal capacity. ★ Activation of hematopoiesis. ▲ proliferation. ⧪ retention in the BM ↝ mobilization ♻ recycling.

Figure 5

Immune cell function in myeloma BM is altered by secreted factors from the MMPCs and the cells lose their normal immune surveillance capacity. An immunosuppressive state is then established, helping MMPCs evade immune system detection. The immune cells show features of exhaustion and anergy. Myeloma cells primarily use secreted IL-6 and TGF-β to disrupt normal immune system activation and express cell adhesion molecules (CAMs) such as PSGL-1, ICAM-1, and VLA-4 which helps in attachment to various immune cells as well as the BMSCs or ECM. PD-L1 is another surface-expressed ligand on MMPCs that can bind NK- and T-cell programmed cell death protein (PD)-1 to suppress their cytotoxic functions and cause immune exhaustion. MMPCs also express CXCL-12 which results in macrophage polarization to M2 or the tumor-associated macrophage phenotype. MMPC-derived cytokines including IL-6 and IL-10, along with secreted M-CSF and VEGF, affect DC maturation and proliferation in the BM. PC = plasma cell, TC = T-cell, NKT = natural killer-like T-cell, Nφ = neutrophil, NK = natural killer cell, MMPC = multiple myeloma plasma cell, Mφ = macrophage, MKφ = megakaryocyte, TAMφ = tumor-associated macrophage, tMKφ = transformed megakaryocyte, DC = dendritic cell, mDC = monocytic DC, pDC = plasmacytoid DC, ExNK = exhausted NK, AnNφ = anergic Nφ, AnTC = anergic TC.

Figure 6

Timeline of therapeutic developments in MM. Historically, corticosteroids were the first drugs to be used in MM treatment, and in the late 1970s, BM stem cell transplantation became one of the most promising treatments in eligible patients. Discovery of the proteasome inhibitor (PI) bortezomib was a significant advancement in MM treatment and remains the standard first-line therapy in most MM regimens today. The last decade has witnessed significant research into targeting the dysregulated immune landscape as well as myeloma cell-specific markers through development of antibody- and cell-based immunotherapeutic approaches.