Immune responses in multiple myeloma: role of the natural immune surveillance and potential of immunotherapies

Abstract

Multiple myeloma (MM) is a tumor of terminally differentiated B cells that arises in the bone marrow. Immune interactions appear as key determinants of MM progression. While myeloid cells foster myeloma-promoting inflammation, Natural Killer cells and T lymphocytes mediate protective anti-myeloma responses. The profound immune deregulation occurring in MM patients may be involved in the transition from a premalignant to a malignant stage of the disease. In the last decades, the advent of stem cell transplantation and new therapeutic agents including proteasome inhibitors and immunoregulatory drugs has dramatically improved patient outcomes, suggesting potentially key roles for innate and adaptive immunity in disease control. Nevertheless, MM remains largely incurable for the vast majority of patients. A better understanding of the complex interplay between myeloma cells and their immune environment should pave the way for designing better immunotherapies with the potential of very long term disease control. Here, we review the immunological microenvironment in myeloma. We discuss the role of naturally arising anti-myeloma immune responses and their potential corruption in MM patients. Finally, we detail the numerous promising immune-targeting strategies approved or in clinical trials for the treatment of MM.

Keywords: Immune escape; Immune responses; Immunotherapy; Multiple myeloma; Tumor microenvironment.

Fig. 1

The MM BM microenvironment. Myeloma microenvironment include bone marrow stromal cells (BMSCs), bone forming (osteoblasts) and resorbing (osteoclasts) cells, the vasculature and immune cells. Reciprocal interactions between BMSCs and MM cells involve cell-to-cell contacts and soluble factors. BMSCs are the main source of IL-6, which is also produced by osteoclasts, tumor associated macrophages (TAMs) or MM cells. IL-6 promotes myeloma cell proliferation, survival and drug resistance. In addition, BMSCs and TAMs secrete vascular endothelial growth factor (VEGF) and thereby favor angiogenesis. Direct and indirect interactions involving MM cells, osteoblasts and osteoclasts imbalance the bone remodeling process and result in bone lysis. Myeloid derived suppressor cells (MDSCs) or regulatory T cells (Tregs) secrete immunosuppressive factors contributing to MM escape from the immune system. Dendritic cells (DCs) prime CD4 and CD8 T cells. Depending on their polarization, CD4 T cells either promote or inhibit tumor growth. IFN-γ secretion by T cells and NK cells may limit MM progression. Furthermore, CD8 T cells and NK cells directly kill tumor cells by releasing cytotoxic granules containing perforin (pfp) and granzymes (Grz)

Fig. 2

MM therapies modulate the immune microenvironment. Thalidomide, IMiDs, Bortezomib and monoclonal antibodies (mAbs) directly regulate tumor cell proliferation and survival. In addition, mAbs induce tumor cell death by triggering NK cell-mediated and tumor associated macrophage (TAM)-mediated antibody dependent cellular cytotoxicity (ADCC). Besides, thalidomide inhibits angiogenesis and both thalidomide and IMiDs decrease the production of pro-inflammatory cytokines by TAMs. IMiDs also promote the anti-MM activity of T cells, NK cells and NKT cells. The impact of bortezomib on anti-myeloma immune responses is unclear. Bortezomib may favor NK cell and dendritic cell (DC) functions by increasing the immunogenicity of MM cells; however toxic effects of bortezomib toward NK cells, DCs and T cells have also been described. Immune checkpoint inhibitors target the immune system to induce potent anti-tumor responses