Natural killer cell biology and therapy in multiple myeloma: challenges and opportunities

Abstract

Despite therapeutic advancements, multiple myeloma (MM) remains incurable. NK cells have emerged as a promising option for the treatment of MM. NK cells are heterogenous and typically classified based on the relative expression of their surface markers (e.g., CD56 and CD16a). These cells elicit an antitumor response in the presence of low mutational burden and without neoantigen presentation via germline-encoded activating and inhibitory receptors that identify the markers of transformation present on the MM cells. Higher NK cell activity is associated with improved survival and prognosis, whereas lower activity is associated with advanced clinical stage and disease progression in MM. Moreover, not all NK cell phenotypes contribute equally toward the anti-MM effect; higher proportions of certain NK cell phenotypes result in better outcomes. In MM, the proportion, phenotype, and function of NK cells are drastically varied between different disease stages; this is further influenced by the bone marrow microenvironment, proportion of activating and inhibitory receptors on NK cells, expression of homing receptors, and bone marrow hypoxia. Antimyeloma therapies, such as autologous stem cell transplant, immunomodulation, proteasome inhibition, and checkpoint inhibition, further modulate the NK cell landscape in the patients. Thus, NK cells can naturally work in tandem with anti-MM therapies and be strategically modulated for improved anti-MM effect. This review article describes immunotypic and phenotypic differences in NK cells along with the functional changes in homeostatic and malignant states and provides expert insights on strategies to harness the potential of NK cells for improving outcomes in MM.

Keywords: Immunomodulation; Multiple myeloma; Natural killer cell activating receptor; Natural killer cell engagers; Natural killer cell inhibitory receptor; Natural killer cells.

Fig. 1

Effect of MM on NK cells: Significantly increased (↑) or decreased (↓) expression of surface markers on NK cells and RRMM cells [13]. CCL, CC-chemokine ligand; CCR, chemokine receptor; CD, cluster of differentiation; CXCL, CXC motif ligand; CXCR, CXC chemokine receptor; CX₃CR, CX3C motif chemokine receptor; DL, domain long cytoplasmic tail; DNAM-1, DNAX accessory molecule-1; DS, domain short cytoplasmic tail; GITR, glucocorticoid-induced TNFR-related protein; HLA, human leukocyte antigen; ICOS, inducible T cell costimulatory; IL, interleukin; KIR, killer immunoglobulin like receptors; MHC, major histocompatibility complex; MM, multiple myeloma; NK, natural killer cell; PD-1, programmed cell death protein 1; PD-L1, programmed death ligand 1; PGE2, prostaglandin E2; RRMM, relapsed/refractory multiple myeloma; sMICA, soluble MHC class I chain-related gene A; SLAMF 7, signaling lymphocyte activation molecular family 7; TGF-β, transforming growth factor beta; TIGIT, T-cell Ig and ITIM domain; TIM3, T cell immunoglobulin

Fig. 2

Effect of antimyeloma therapy on NK cells. 1. Autologous stem cell transfer. NK cells rapidly reconstitute after ASCT. Post-ASCT, NK cells show an increase in proliferative capacity and phenotypic redistribution, resulting in an increase in CD56^dim CD16⁺ NK cell frequency (adapted from Trans and Cell Ther 28 (2022) 310.e1-310.e6) [70]. 2. Corticosteroids. Corticosteroids (dexamethasone) inhibit the development, proliferation, and function of NK cells in MM. Concomitant use of dexamethasone with lenalidomide inhibits the immunomodulatory effects (NK cell activating ability) of lenalidomide and also downregulate NKG2D, NKp46 and DNAM1. However, dexamethasone increases NK cell proliferation, CD16⁺ and DNAM1^bright NK cell numbers, CD94 or NKG2A expression in the presence of IL2 and IL12. 3. Immunomodulatory drugs. IMiDs increase the activation and proliferation of NK cells (CD56^dim NK cells increase) as well as repair of lytic synapse. Apart from the antimyeloma effect, IMiDs produce costimulatory effects on NK cells, resulting in increased NK cell number. IMiDs also enhance NK cell cytotoxicity by ZAP-70-mediated CD56^dim NK cell increase, and upregulation of GZM-B, and IFNγ. 4. Proteasome inhibitors. PIs sensitize NK cells against myeloma cells by upregulation NKG2 ligands and DNAM1-L. Calreticulin, an NKp46 ligand, can be externalized by the induction of ER stress pathway. ER stress also induces DR5 expression and enhances TRAIL-mediated killing of myeloma cells. Bortezomib causes apoptosis of primary resting NK cells by inducing ROS production and reducing NKp46 receptor expression. as well as NK cell cytotoxicity-mediated by the NKp46 activation (adapted from Front. Cell Dev. Biol. 12:1359084) [71]. 5. Monoclonal antibodies. CD38 monoclonal antibodies (daratumumab and isatuximab) cause fratricide of CD38^high NK-cells. Majority of NK cells (85 ~ 90%) express CD38 and are targeted by CD38 antibodies. The residual CD38^low/− NK cell population (3–10%) are resistant to fratricide and show high proliferative and cytotoxic activity. The effector CD38^low/− NK cells show a high proliferative potential and functional activity in the presence of CD38 mAb by inducing ADCC. However, the NK cells recover once the treatment is discontinued (adapted from Int J Bio Sci 18 [5]:1974–1988) [72]. SLAMF7 targeting monoclonal antibodies (elotuzumab) acts by antibody dependent cellular cytotoxicity. SLAMF7 is also expressed on NK cells, where it acts as an activating receptor via interaction with signaling adaptor protein, EWS-activated transcript 2 (adapted from Clin Transl Sci (2018) 11, 261–266) [73]. ADCC, antibody-dependent cellular cytotoxicity; ASCT, autologous stem cell transfer; ATM/ATR, ataxia-telangiectasia mutated/RAD3-related; CD, cluster of differentiation; DNAM1, DNAX accessory molecule; DR, death receptor; EAT2, EWS-activated transcript 2; ER, endoplasmic reticulum; FasL, Fas ligand; GZM-B, granzyme B; HLA, human leukocyte antigen; IFN-γ, interferon gamma; IL, interleukin; IMiD, immunomodulatory drugs; MM, multiple myeloma; NK, natural killer; PI, proteasome inhibitor; ROS, reactive oxygen species; SLAMF7, signaling lymphocyte activation molecule family member 7; TRAIL, tumor necrosis factor related apoptosis-inducing ligand; ZAP-70, Zeta-chain-associated protein kinase 70