The Immune Microenvironment in Multiple Myeloma: Friend or Foe?

Abstract

Multiple myeloma (MM) is one of the most prevalent hematological cancers worldwide, characterized by the clonal expansion of neoplastic plasma cells in the bone marrow (BM). A combination of factors is implicated in disease progression, including BM immune microenvironment changes. Increasing evidence suggests that the disruption of immunological processes responsible for myeloma control ultimately leads to the escape from immune surveillance and resistance to immune effector function, resulting in an active form of myeloma. In fact, one of the hallmarks of MM is the development of a permissive BM milieu that provides a growth advantage to the malignant cells. Consequently, a better understanding of how myeloma cells interact with the BM niche compartments and disrupt the immune homeostasis is of utmost importance to develop more effective treatments. This review focuses on the most up-to-date knowledge regarding microenvironment-related mechanisms behind MM immune evasion and suppression, as well as promising molecules that are currently under pre-clinical tests targeting immune populations.

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

“…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].…”

“…Overall, it has been reported that a higher percentage of CD4+ T cells can be found in the BM of patients with newly diagnosed MM or high-risk SMM (but not with MGUS) as compared to HD [28].…”

“…pDCs are specialized in the production of type I IFN in response to specific stimuli such as viruses; on the other hand, by releasing particular context-dependent cytokines and through MHCdependent and independent cell-to-cell interaction, mDCs orchestrate the differentiation and polarization of different populations of T lymphocytes, such as Th1, Th2, Th17, CTL, and Tregs [14,22,23,28,50]. Additionally, mDCs can also interact with NK and B cells and are involved in the development of local and systemic inflammation as well as autoimmune disease and cancer [14,22,23,28,50]. It is essential to figure out how DCs are usually regulated and how this regulation may be compromised within cancer IM to understand their potential dual role (as tumor-suppressors or tumor-promoting cells) in MM fully.…”

“…Cytotoxic T lymphocytes (CD8 + T cells) are considered the effectors of the adaptive immune system, being in charge of the protection against intracellular infections (either bacteria or virus) and the elimination of malignant cells. Interestingly, once the target cells have been eliminated, few antigen-specific CTLs survive transformed in memory cells, ready to be re-activated if and when needed [22,23,25,28]. In MM patients, CTLs have been found to be increased in both MGUS and symptomatic MM (with respect to healthy donors) but dysfunctional (in term of proliferation and cytotoxic activity), presenting a reduced capability to respond to antigenic stimuli.…”

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“…MM also stimulates osteoclasts in the bones via the nuclear factor kappa-B ligand (RANKL), resulting in the destruction of bone via lytic lesions that cause pain, fractures, mobility issues and calcinosis. The hallmark end-organ damage of MM is referred to as “CRAB” symptoms: hypercalcemia, renal involvement, anemia, and bone lesions [ 14 ].…”