The cellular immune system in myelomagenesis: NK cells and T cells in the development of myeloma [corrected] and their uses in immunotherapies

Abstract

As vast strides are being made in the management and treatment of multiple myeloma (MM), recent interests are increasingly focusing on understanding the development of the disease. The knowledge that MM develops exclusively from a protracted phase of monoclonal gammopathy of undetermined significance provides an opportunity to study tumor evolution in this process. Although the immune system has been implicated in the development of MM, the scientific literature on the role and status of various immune components in this process is broad and sometimes contradictory. Accordingly, we present a review of cellular immune subsets in myelomagenesis. We summarize the current literature on the quantitative and functional profiles of natural killer cells and T-cells, including conventional T-cells, natural killer T-cells, γδ T-cells and regulatory T-cells, in myelomagenesis. Our goal is to provide an overview of the status and function of these immune cells in both the peripheral blood and the bone marrow during myelomagenesis. This provides a better understanding of the nature of the immune system in tumor evolution, the knowledge of which is especially significant considering that immunotherapies are increasingly being explored in the treatment of both MM and its precursor conditions.

Figure 1

Schematic of functional interactions of NK-cells and T-cells with malignant plasma cells. The functional cytotoxicity of NK-cells against malignant plasma cells is inhibited by malignant plasma cells via the activation of Tregs. MM cells evade cytotoxicity via a lack of HLA Class I loss and the shedding of the surface antigen MICA, which leads to downregulation of the NKG2D activating receptor on NK-cells, cytotoxic T-cells and γδ-T-cells. mAbs and IMiDs rely on NK-cell-mediated ADCC to exert some of their anti-MM effects. Promising targets for NK-mediated immunotherapies against malignant plasma cells include the PD-1/PD-L1 axis and CS1. Circulating MICA is shed by malignant plasma cells upon progression from MGUS to MM and downregulates NKG2D on cytotoxic T-cells, NK-cells and γδ-T-cells. NKT-cells exhibit decreased cytotoxicity from MGUS to MM as evidenced by a loss of IFN-γ production and decreased CD1d-mediated targeting of malignant plasma cells. However, NKT-cells may be stimulated by extrinsic α-GalCer and IMiDs. γδ-T-cells are activated by bisphosphonates and IL-2. Th1 cells are inhibited by IL-6 produced by malignant plasma cells and Th17 cells have a role in the development of bony lytic lesions in MM. Plus and minus signs indicate stimulation or inhibition of pathway demonstrated by arrows, respectively.