Overcoming the Immunosuppressive Tumor Microenvironment in Multiple Myeloma

Abstract

SeverFigurel cellular elements of the bone marrow (BM) microenvironment in multiple myeloma (MM) patients contribute to the immune evasion, proliferation, and drug resistance of MM cells, including myeloid-derived suppressor cells (MDSCs), tumor-associated M2-like, “alternatively activated” macrophages, CD38+ regulatory B-cells (Bregs), and regulatory T-cells (Tregs). 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. Immunomodulatory imide drugs (IMiDs), protease inhibitors (PI), monoclonal antibodies (MoAb), adoptive T-cell/NK cell therapy, and inhibitors of anti-apoptotic signaling pathways have emerged as promising therapeutic platforms that can be employed in various combinations as part of a rationally designed immunomodulatory strategy against an immunosuppressive tumor microenvironment (TME) in MM. These platforms provide the foundation for a new therapeutic paradigm for achieving improved survival of high-risk newly diagnosed as well as relapsed/refractory MM patients. Here we review the scientific rationale and clinical proof of concept for each of these platforms.

Targeting Reactive Oxygen Species Metabolism to Induce Myeloma Cell Death

“…TME displays also tumor-promoting activity by allowing the polarization of M2 macrophages and inhibiting regulatory T cells (Tregs). Several recent reviews are dedicated to this theme [148,[196][197][198], we rapidly report here some important clues. The PD-1/PD-L1 pathway controls, at least in part, the maintenance of immune surveillance within the TME [199].…”

TREM2: Keeping Pace With Immune Checkpoint Inhibitors in Cancer Immunotherapy

“…In order to be fit for cancer cell survival, tumors would coopt myeloid cells, which constitute an important cellular fraction of TME, to suppress the immune system through various mechanisms and then negatively regulate anti-tumor immune function (61,62). It's worth noting that recent studies have demonstrated that tumor-infiltrating myeloid cells are heterogeneous and may actually contain both immunostimulatory subpopulation and immunosuppressive subpopulation (63,64), and MDSCs which can be subdivided as macrophages, granulocytes (especially neutrophils but occasionally and less numerous basophils and mast cells), monocytes and DCs are a immunosuppressive myeloid cell population characterized by the function of promoting tumor growth in tumor immune network (63,65), this subpopulation also has been reported in relation to the resistance to immunotherapy such as ICIs (66).…”

Dual Targeting of Multiple Myeloma Stem Cells and Myeloid-Derived Suppressor Cells for Treatment of Chemotherapy-Resistant Multiple Myeloma

“…The immunosuppressive bone marrow microenvironment (BMME) in MM contains cellular elements that facilitate the immune evasion of malignant MM clones (9)(10)(11)(12)(13). These immunosuppressive cells include MDSCs, an immature myeloid cell population capable of inhibiting effector cytotoxic T-cell (CTL) populations as well as natural killer (NK) cells and contribute to the T-cell exhaustion which is a hallmark of the BMME in MM patients (4,(14)(15)(16)(17)(18)(19)(20). In addition, regulatory T cells (Tregs), regulatory B-cells (Bregs), and tumor-associated macrophages (TAM) also contribute to BMME-associated immunosuppression (20).…”

“…These immunosuppressive cells include MDSCs, an immature myeloid cell population capable of inhibiting effector cytotoxic T-cell (CTL) populations as well as natural killer (NK) cells and contribute to the T-cell exhaustion which is a hallmark of the BMME in MM patients (4,(14)(15)(16)(17)(18)(19)(20). In addition, regulatory T cells (Tregs), regulatory B-cells (Bregs), and tumor-associated macrophages (TAM) also contribute to BMME-associated immunosuppression (20). The immunosuppressive BMME in MM has been implicated in clonal evolution and immune evasion of MM cells accelerating disease progression (4,20).…”