The Leading Role of the Immune Microenvironment in Multiple Myeloma: A New Target with a Great Prognostic and Clinical Value

Abstract

Multiple myeloma (MM) is a plasma cell (PC) malignancy whose development flourishes in the bone marrow microenvironment (BMME). The BMME components' immunoediting may foster MM progression by favoring initial immunotolerance and subsequent tumor cell escape from immune surveillance. In this dynamic process, immune effector cells are silenced and become progressively anergic, thus contributing to explaining the mechanisms of drug resistance in unresponsive and relapsed MM patients. Besides traditional treatments, several new strategies seek to re-establish the immunological balance in the BMME, especially in already-treated MM patients, by targeting key components of the immunoediting process. Immune checkpoints, such as CXCR4, T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT), PD-1, and CTLA-4, have been identified as common immunotolerance steps for immunotherapy. B-cell maturation antigen (BCMA), expressed on MMPCs, is a target for CAR-T cell therapy, antibody-(Ab) drug conjugates (ADCs), and bispecific mAbs. Approved anti-CD38 (daratumumab, isatuximab), anti-VLA4 (natalizumab), and anti-SLAMF7 (elotuzumab) mAbs interfere with immunoediting pathways. New experimental drugs currently being evaluated (CD137 blockers, MSC-derived microvesicle blockers, CSF-1/CSF-1R system blockers, and Th17/IL-17/IL-17R blockers) or already approved (denosumab and bisphosphonates) may help slow down immune escape and disease progression. Thus, the identification of deregulated mechanisms may identify novel immunotherapeutic approaches to improve MM patients' outcomes.

Keywords: bone marrow niche; immune checkpoint inhibitors; immune escape; immune exhaustion; immune microenvironment; immunotherapy; multiple myeloma.

Figure 1

The bone marrow microenvironment (BMME) in multiple myeloma (MM). Complex interactions between non-hematopoietic stromal cells and BM immune system may support pro- and anti-tumor events in the BMME, highlighting the roles of immune components in the impaired anti-MM immune responses and disease progression. Innate and adaptive immune cells can recognize malignant plasma cells (PCs) and generate an anti-tumor immune response against tumors. A predominant role is attributed to immune cells, such as CD4⁺ Tregs and T cytotoxic CD8⁺ cells, which are considered effectors of host control for the MM PCs.

Figure 2

The bone marrow microenvironment (BMME) in multiple myeloma (MM). In BMME, plasmacytoid and conventional dendritic cells (pDCs and cDCs) play an important role in activating tumor-specific T cells with natural killer (NK), NKT phenotype, and gamma delta (γδ) T cells, inducing INF-γ production. Concomitantly, CD8⁺ and CD4⁺ cells realize an immunosuppressive milieu, producing transforming growth factor (TGF)-β, vascular-endothelial growth factor (VEGF), interleukin (IL)-10, IL-6, IL-17, and IL-2; interacting with antigen-presenting cells (APCs); and inducing T regulatory (Treg) cell differentiation and proliferation. The same interaction stimulates the CD28-CD80/CD86 contact and decreases the processing and presentation of tumor antigens, thus reducing malignant PC recognition by cytotoxic T CD8⁺ cells. Stromal cells, such as endothelial cells (ECs), fibroblasts (FBs), mesenchymal stem cells (MSCs), DCs, myeloid-derived suppressor cells (MDSCs), osteoclasts, and tumor-associated macrophages (TAMs), alongside immune cells, regulate different mechanisms (i.e., cell-to-cell adhesion; release of soluble factors, cytokines, chemokines, and growth factors) and activate several signaling pathways leading to MM progression. Among them, note that MSC-derived microvesicles are introjected by malignant PCs; B-cell maturation antigen (BCMA), CD38, and SLAMF7 are hyper-expressed on malignant PCs; osteoclasts highly activate and release RANK-L, Gal-9, and APRIL; VLA4 is expressed on FBs; CD137, CD226 (interacting with CD112 and CD155 on malignant PCs), and NKG2D (interacting with MICA\B on malignant PCs) are expressed on NK and CD8⁺ cells.

Figure 3

Immunomodulatory drugs in MM. Tumors have been shown to evade the immune system. This has led to the development of new agents to be used in combination with both well-established and innovative therapeutical schemes. Some of these immunological drugs include anti-CTLA-4 (ipilimumab), anti-CXCR4/CSCL12 system (ulocuplumab and olaptesed pegol), anti-PD-1/PDL-1 (nivolumab and pembrolizumab), and TIGIT, which counteract the blockade caused by immune checkpoints, enhance the immune response, and induce selective control on tumor growth, sometimes in the long term. As a result, the immune system is more active in recognizing the tumor as a foreign entity. CAR-T therapy is directed against the B-cell maturation antigen (BCMA) found on the surface of cancer cells; recognition and binding of BCMA lead to the proliferation of CAR-T cells, which can thus attack and kill the cancer cells expressing this antigen. Recent agents with the same target are Ab-drug conjugates (ADCs) and bispecific monoclonal Abs (such as BiTEs). A long list of mAbs capable of interfering with immunoediting pathways is currently approved, especially in combination regimes, and includes anti-CD38 (daratumumab and isatuximab), anti-VLA4 (natalizumab), and anti-SLAMF7 (elotuzumab) drugs; in addition, several new experimental compounds are currently under evaluation, such as CD137 blockers, MSC-derived microvescicle blockers, CSF-1/CSF-1R system blockers, and Th17/IL-17/IL-17R system blockers. Lastly, denosumab and bisphosphonates have been shown to be effective in slowing clinical disease progression and the immune escape process.