Immune System Alterations in Multiple Myeloma: Molecular Mechanisms and Therapeutic Strategies to Reverse Immunosuppression

Multiple myeloma (MM) is a common hematological disease characterized by the accumulation of clonal malignant plasma cells in the bone marrow. Over the past two decades, new therapeutic strategies have significantly improved the treatment outcome and patients survival. Nevertheless, most MM patients relapse underlying the need of new therapeutic approaches. Plasma cells are prone to produce large amounts of immunoglobulins causing the production of intracellular ROS. Although adapted to high level of ROS, MM cells die when exposed to drugs increasing ROS production either directly or by inhibiting antioxidant enzymes. In this review, we discuss the efficacy of ROS-generating drugs for inducing MM cell death and counteracting acquired drug resistance specifically toward proteasome inhibitors.

Section: Global Alteration Of MM Metabolismmentioning

confidence: 73%

Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death

Caillot

Dakik

Mazurier

et al. 2021

“…An increase in MDSCs in peripheral blood and BM aspirates from MM patients (as compared to MGUS or healthy donors) has been reported [26,27]. Furthermore, along with disease evolution, an increase in the activation of the JAK/STAT signaling in response to MM cells exposure has been observed, which, coupled with MDSCs' capability to differentiate into "osteoclast-like" cells to deplete arginine from the microenvironment through overexpression of arginase-1 and to increase nitric oxide production, supports the establishment of a proinflammatory and tolerogenic niche as well as the generation of lytic bone lesions [15,24,25,28].…”

Section: Mdscsmentioning

confidence: 91%

“…Indeed, despite the recent introduction of novel drugs, which improved the clinical outcome of MM patients, the disease remains incurable, and novel "microenvironment oriented" strategies are eagerly awaited [11]. Accordingly, the possibility to modulate the inflammatory microenvironment as well as the immune system by either recovering the tumor-associated immunosuppression or enhancing the anti-cancer immune-response represents an emerging and effective opportunity to induce long-lasting clinical benefits in different malignancies [25].…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities

Botta

Mendicino

Martino

et al. 2021

Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by a multi-step evolutionary path, which starts with an early asymptomatic stage, defined as monoclonal gammopathy of undetermined significance (MGUS) evolving to overt disease in 1% of cases per year, often through an intermediate phase known as “smoldering” MM (sMM). Interestingly, while many genomic alterations (translocation, deletions, mutations) are usually found at early stages, they are not sufficient (alone) to determine disease evolution. The latter, indeed, relies on significant “epigenetic” alterations of different normal cell populations within the bone marrow (BM) niche, including the “evasion” from immune-system control. Additionally, MM cells could “educate” the BM immune microenvironment (BM-IM) towards a pro-inflammatory and immunosuppressive phenotype, which ultimately leads to disease evolution, drug resistance, and patients’ worse outcome. Indeed, it is not a case that the most important drugs for the treatment of MM include immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide) and monoclonal antibodies (daratumumab, isatuximab, and elotuzumab). On these bases, in this review, we describe the most recent advances in the comprehension of the role of the different cells composing the BM-IM, and we discuss the potential molecular targets, which could represent new opportunities to improve current treatment strategies for MM patients.

“…On the other hand, immunosuppression is a common feature of MM patients associated with the evolution of the disease [ 197 , 198 ]. This immunosuppression is mediated by high concentrations of immunosuppressive soluble factors, loss of effective antigen presentation, effector cell dysfunction, and by the recruitment of immunosuppressive populations, such as myeloid-derived suppressor cells (MDSCs) [ 199 , 200 ].…”

Section: Biological Roles Of Mscs In MM Pathologymentioning

confidence: 99%

“…These MDSCs produced upregulated immunosuppressive factors (e.g., Arginase1 and TNFα) [ 49 ] and increased ability to digest bone matrix [ 202 ]. Furthermore, these MDSCs have been reported to support MM progression by suppressing T cell responses, inducing Treg differentiation, and even differentiating into OCs (see review [ 197 ]). Of interest, MM-MSCs derived exosomes were able to activate MDSCs in the BM and increased their survival by activating STAT3 and STAT1 pathways and increasing BCL-X L and MCL-1 levels.…”

Section: Biological Roles Of Mscs In MM Pathologymentioning

confidence: 99%

Bone Marrow Mesenchymal Stromal Cells in Multiple Myeloma: Their Role as Active Contributors to Myeloma Progression

Maiso

Mogollón

Ocio

et al. 2021

Self Cite

Multiple myeloma (MM) is a hematological malignancy of plasma cells that proliferate and accumulate within the bone marrow (BM). Work from many groups has made evident that the complex microenvironment of the BM plays a crucial role in myeloma progression and response to therapeutic agents. Within the cellular components of the BM, we will specifically focus on mesenchymal stromal cells (MSCs), which are known to interact with myeloma cells and the other components of the BM through cell to cell, soluble factors and, as more recently evidenced, through extracellular vesicles. Multiple structural and functional abnormalities have been found when characterizing MSCs derived from myeloma patients (MM-MSCs) and comparing them to those from healthy donors (HD-MSCs). Other studies have identified differences in genomic, mRNA, microRNA, histone modification, and DNA methylation profiles. We discuss these distinctive features shaping MM-MSCs and propose a model for the transition from HD-MSCs to MM-MSCs as a consequence of the interaction with myeloma cells. Finally, we review the contribution of MM-MSCs to several aspects of myeloma pathology, specifically to myeloma growth and survival, drug resistance, dissemination and homing, myeloma bone disease, and the induction of a pro-inflammatory and immunosuppressive microenvironment.