The Role of Tumor Microenvironment in Multiple Myeloma Development and Progression

Abstract

Multiple myeloma (MM) is a hematologic cancer characterized by clonal proliferation of plasma cells in the bone marrow (BM). The progression, from the early stages of the disease as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM and occasionally extramedullary disease, is drastically affected by the tumor microenvironment (TME). Soluble factors and direct cell–cell interactions regulate MM plasma cell trafficking and homing to the BM niche. Mesenchymal stromal cells, osteoclasts, osteoblasts, myeloid and lymphoid cells present in the BM create a unique milieu that favors MM plasma cell immune evasion and promotes disease progression. Moreover, TME is implicated in malignant cell protection against anti-tumor therapy. This review describes the main cellular and non-cellular components located in the BM, which condition the immunosuppressive environment and lead the MM establishment and progression.

Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

“…Several cellular elements of the bone marrow (BM) microenvironment in MM patients contribute to the immune evasion, proliferation, and drug resistance of MM cells [4][5][6], including myeloid-derived suppressor cells (MDSCs), tumor-associated M2-like, "alternatively activated", macrophages, CD38 + regulatory B-cells (Bregs), and regulatory T-cells (Tregs) [4][5][6] (Figure 1A). These immunosuppressive elements in bidirectional and multi-directional crosstalk with each other inhibit both memory and cytotoxic effector T-cell populations as well as natural killer (NK) cells [4][5][6]. MDSCs along with MM cellderived interleukin 10 (IL-10) [7][8][9][10], TGF-β, and IL-6 are also known to impair dendritic cell (DC) maturation and their antigen-presenting function, which further accentuates with MM cell-derived interleukin 10 (IL-10) [7][8][9][10], TGF-, and IL-6 are also known to impair dendritic cell (DC) maturation and their antigen-presenting function, which further accentuates the immunosuppression [6].…”

“…The tumor microenvironment (TME) is one of the main contributors of a marked immunobiological and clinical heterogeneity as well as clonal evolution in multiple myeloma (MM) [ 1 , 2 , 3 ]. Several cellular elements of the bone marrow (BM) microenvironment in MM patients contribute to the immune evasion, proliferation, and drug resistance of MM cells [ 4 , 5 , 6 ], including myeloid-derived suppressor cells (MDSCs), tumor-associated M2-like, “alternatively activated”, macrophages, CD38 + regulatory B-cells (Bregs), and regulatory T-cells (Tregs) [ 4 , 5 , 6 ] ( Figure 1 A). These immunosuppressive elements in bidirectional and multi-directional crosstalk with each other inhibit both memory and cytotoxic effector T-cell populations as well as natural killer (NK) cells [ 4 , 5 , 6 ].…”

Monocyte Subsets and Serum Inflammatory and Bone-Associated Markers in Monoclonal Gammopathy of Undetermined Significance and Multiple Myeloma

“…At present, it is well-established that both the immune and bone microenvironment play a key role in the pathogenesis of PC neoplasms [4,5]. Among other immune cells [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45], Mo [25,26,50] and macrophages [6,7,9] have emerged as key players in disrupting normal BM and bone homeostasis.…”

“…Among other immune cells [30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45], Mo [25,26,50] and macrophages [6,7,9] have emerged as key players in disrupting normal BM and bone homeostasis. This translates into increased levels in serum of multiple inflammatory cytokines [27,28] and markers [11][12][13][14][15][16][17][18]21,22] associated with increased bone resorption, particularly in MM [4,5]. In parallel, important advances have been achieved in the understanding of the maturation pathways leading to the production of Mo in BM and their heterogeneity in blood and BM, including the functional role of the many subsets of Mo identified so far [48,[51][52][53][54][55][56][57][58].…”

“…Tumor PC control and growth kinetics in both MGUS and MM depend both on the intrinsic characteristics of neoplastic PC and their close interaction with the tumor microenvironment [4,5]. Thus, malignant BM PC in MM, and to a less extent also in MGUS and SMM, have the ability to modify their surrounding immune and bone microenvironment, interfere with immune surveillance and ultimately lead to bone resorption and lysis via direct local cell-to-cell and cytokine-mediated interactions between monocyte/macrophages, stromal cells, osteoclasts and osteoblasts [6,7].…”