Natural killer cells affect the natural course, drug resistance, and prognosis of multiple myeloma

Abstract

Multiple myeloma (MM), a stage-developed plasma cell malignancy, evolves from monoclonal gammopathy of undetermined significance (MGUS) or smoldering MM (SMM). Emerging therapies including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, chimeric antigen-T/natural killer (NK) cells, bispecific T-cell engagers, selective inhibitors of nuclear export, and small-molecule targeted therapy have considerably improved patient survival. However, MM remains incurable owing to inevitable drug resistance and post-relapse rapid progression. NK cells with germline-encoded receptors are involved in the natural evolution of MGUS/SMM to active MM. NK cells actively recognize aberrant plasma cells undergoing malignant transformation but are yet to proliferate during the elimination phase, a process that has not been revealed in the immune editing theory. They are potential effector cells that have been neglected in the therapeutic process. Herein, we characterized changes in NK cells regarding disease evolution and elucidated its role in the early clinical monitoring of MM. Additionally, we systematically explored dynamic changes in NK cells from treated patients who are in remission or relapse to explore future combination therapy strategies to overcome drug resistance.

Keywords: NK cells; autologous hematopoietic stem cell transplantation; chimeric antigen receptor cells; immunomodulatory drugs; monoclonal antibodies; multiple myeloma; proteasome inhibitors.

FIGURE 1

The origins of multiple myeloma (MM). Before developing MM, abnormal cells in the germinal center (GC) endure a lengthy pro-monoclonal gammopathy of undetermined significance (MGUS) phase. B cells originating from GC proliferate rapidly in the dark zone (DZ), undergo class switch recombination (CSR) and somatic hypermutation (SHM), and are subsequently selected by follicular dendritic cell (FDC) in the light zone (LZ), re-entering the DZ to undergo repeated cyclic re-entry processes (Basso, 2021; Pasqualucci and Klein, 2022). After accumulating generation by generation, a clone that has acquired a critical mutation leaves the GC and, subsequently, re-enters the GC to acquire the initiating mutation (Maura et al., 2021; Ho et al., 2022). Finally, the clone, independent of the GC, moves to the bone marrow (BM) by chemokines and then begins to evolve from MGUS to smoldering MM (SMM) to active MM.

FIGURE 2

Interplay between myeloma cells and natural killer (NK) cells. After progression to active multiple myeloma (MM), NK cells are progressively depleted, with a decrease in numbers, inhibitory and activating receptor imbalance, functional inhibition, and chemokine imbalance. The combination of impaired NK cell proliferation and NKG2D-NKG2DL axis-induced fratricide led to decreased cell numbers (Seymour et al., 2022). The levels of NK cell activating receptors NCR3, NKG2D, 2B4, and DNAM-1 are reduced, while inhibiting receptor PD-1 are increased (Seymour et al., 2022). On the target cells, the inhibitory mediators MHC I and PD-L1 are also upregulated. Severe imbalance of activating and inhibiting receptors leads to functional inhibition. This alteration is associated with cytokines and hypoxia. Physical contact between osteoblasts and NK cells increases interleukin (IL)-6 and IL-10 production (Uhl et al., 2022). Regulatory T cells (Tregs) and bone marrow (BM)-derived suppressor cells release TGF-β (Ghiringhelli et al., 2005). This results in the formation of an extensive immunosuppressive microenvironment. Hypoxia decreases NKG2D and CD16 expression and impairs NK cell degranulation (Sarkar et al., 2013). Sialic acid-binding immunoglobulin-like lectin (Siglec) ligand (PSGL-1/CD43) on MM cells binds to inhibitory Siglec-7 on NK cells, inhibiting cytotoxicity and cytokine production by activating the phosphatase SHP-1/2 in NK cells (Daly et al., 2022a; Daly et al., 2022b). Downregulation of C-X-C motif chemokine (CXCL)12 and its ligand C-X-C chemokine receptor type 4 (CXCR4) affects NK cell trafficking in the BM and weakens antitumor immune responses at the primary tumor site (Ponzetta et al., 2015; Tomaipitinca et al., 2021).

FIGURE 3

Natural killer (NK) cell changes after proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and monoclonal antibodies (mAbs) treatment. (A). Bortezomib can up- or downregulate the expression of ligands associated with NK cell activation sensitizing myeloma cells to recognize NK cells (Soriani et al., 2009; Yang et al., 2015; Niu et al., 2017), meanwhile, bortezomib inhibits the responses of NK cells to sensitized tumor cells by inducing apoptosis, decreasing activating ligand expression, and inhibiting non-perforin killing (Wang et al., 2009). (B). Directly, lenalidomide alters NK cell immune phenotype and adjusts the ratio of CD56bright/dim NK cell subsets; lenalidomide activates Zap-70 in NK cells to upregulate GZM-B and increases the porous region of the actin-network to promote the release of interferon (IFN)-γ-containing vesicles (Giuliani et al., 2017; Hideshima et al., 2021); indirectly, lenalidomide promotes the proliferation and activation of NK cells by regulating the complex signaling pathways of effector cells such as T cells, NK cells, and natural killer T (NKT) cells to promote IL-2 and IFN-γ release (LeBlanc et al., 2004; Zhu et al., 2019). (C). Daratumumab induced CD38⁺ NK cell fratricide via the antibody-dependent cell-mediated cytotoxicity effects of NK–NK cells (Wang et al., 2018). (D). elotuzumab activates NK cells by directly binding to SLAMF7; SLAMF7-SLAMF7 interaction between NK cells and myeloma cells induced NK cell activation and promoted cytotoxicity (Malaer and Mathew, 2017).