Dissecting molecular mechanisms of immune microenvironment dysfunction in multiple myeloma and precursor conditions

Abstract

Multiple myeloma (MM) is a disease of clonally differentiated plasma cells. MM is almost always preceded by precursor conditions, monoclonal gammopathy of unknown significance (MGUS), and smoldering MM (SMM) through largely unknown molecular events. Genetic alterations of the malignant plasma cells play a critical role in patient clinical outcomes. Del(17p), t(4;14), and additional chromosomal alterations such as del(1p32), gain(1q) and MYC translocations are involved in active MM evolution. Interestingly, these genetic alterations appear strikingly similar in transformed plasma cell (PC) clones from MGUS, SMM, and MM stages. Recent studies show that effectors of the innate and adaptive immune response show marked dysfunction and skewing towards a tolerant environment that favors disease progression. The MM myeloid compartment is characterized by myeloid-derived suppressor cells (MDSCs), dendritic cells as well as M2-like phenotype macrophages that promote immune evasion. Major deregulations are found in the lymphoid compartment as well, with skewing towards immune tolerant Th17 and Treg and inhibition of CD8+ cytotoxic and CD4+ activated effector T cells. In summary, this review will provide an overview of the complex cross-talk between MM plasma cells and immune cells in the microenvironment and the molecular mechanisms promoting progression from precursor states to full-blown myeloma.

Keywords: Multiple myeloma; immune response; immune-microenvironment; immunotherapy; plasma cells.

Figure 1.

FDA-approved drugs for multiple myeloma and date of their first approval.

Figure 2.

Myeloid cells in MM niche. Cartoon representing the cross-talk between myeloid derived suppressor cells (MDSC), dendritic cells (DC), Tumor-associated macrophages 2 (TAM M2) with MM plasma cells (PC) and Th17, T regulatory cells (Treg), Th17, cytotoxic CD8+ cells and natural killer cells (NK).

Figure 3.

Lymphoid cells in multiple myeloma niche. Cartoon representing the interaction between lymphoid compartment and MM plasma cells (PC). Cytotoxic T cells CD8+ and regulatory T cells (Treg) in multiple myeloma have increased expression of immunosuppression molecules, with suppression of B cells, APC and NK cells activity.

Figure 4.

Other microenvironment components. (A) Inflammatory mesenchymal stromal cells (iMSCs): IL-1, TNF-alfa secreted by myeloid cells, cytotoxic T cells and NK cells and DAMPs deriving from tumor cells induce inflammatory phenotype of stromal cells. In turn, iMSC support tumor development through secretion of IL-6, LIF, CCL2 among other cytokines. iMSC simultaneously recruit and modulate immune cells, primarily myeloid cells. (B) osteoclasts: upregulation of Gal-9, CD200, HVEM, CD200, PD-L1, RANK in osteoclasts with secretion of IDO induce immuno-suppression; osteoclasts also produce OPN, IL-6, BAFF and APRIL that support MM survival. (C) Exosomes: BM cells in MM compared to healthy donors showed lower levels of miRNA-15a and increased levels of pro-tumoral Il-6, fibronectin, and CCL-2.