Alterations of NK Cell Phenotype in the Disease Course of Multiple Myeloma

Abstract

Accumulating evidence demonstrates important roles for natural killer (NK) cells in controlling multiple myeloma (MM). A prospective flow cytometry-based analysis of NK cells in the blood and bone marrow (BM) of MM patient subgroups was performed (smoldering (SMM), newly diagnosed (ND), relapsed/refractory, (RR) and post-stem cell transplantation (pSCT)). Assessments included the biomarker expression and function of NK cells, correlations between the expression of receptors on NK cells with their ligands on myeloma cells, and comparisons between MM patient subgroups and healthy controls. The most striking differences from healthy controls were found in RR and pSCT patients, in which NK cells were less mature and expressed reduced levels of the activating receptors DNAM-1, NKG2D, and CD16. These differences were more pronounced in the BM than in blood, including upregulation of the therapeutic targets TIM3, TIGIT, ICOS, and GITR. Their expression suggests NK cells became exhausted upon chronic encounters with the tumor. A high expression of SLAMF7 on blood NK cells correlated with shorter progression-free survival. This correlation was particularly evident in ND patients, including on mature CD56dim NK cells in the BM. Thus, our NK cell analysis identified possible therapeutic targets in MM and a biomarker with prognostic potential for disease progression.

Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities

“…Accordingly, the most active drugs for MM treatment or for reducing the risk of evolution from sMM to MM include agents with strong activity on the microenvironment, such as immunomodulatory drugs (IMiDs) or monoclonal antibodies [10,11]. In this context, much evidence supports the critical role played by stromal cells [12,13] and different cells of the IM (such as dendritic cells [14], myeloid-derived suppressor cells (MDSCs) [15,16], natural killer [17], and specific lymphocytes subclasses including the pro-inflammatory Th17 cells [18,19]) as well as BM-extrinsic drivers such as the microbiota [20] in driving MM evolution. Gut microbiota, particularly by promoting chronic inflammation and/or immune suppression, could drive non-aerodigestive tract malignancies with mechanisms that are still under active investigation and have been recently identified as a new player in determining tumor progression [20,21].…”

Harnessing the Immune System to Fight Multiple Myeloma

“…In particular, the importance of NK cells in MM control has been demonstrated in several studies [25][26][27]. Accordingly, NK cells from MM patients show both quantitative and qualitative changes compared to NK cells from healthy donors [28,29]. Taken together, this evidence paints a complex picture where progressive immunosuppression associates with MM development.…”

Defucosylation of Tumor-Specific Humanized Anti-MUC1 Monoclonal Antibody Enhances NK Cell-Mediated Anti-Tumor Cell Cytotoxicity

“…Still, lower baseline levels of CD16 correlate with decreased ADCC responses in NK cells: compared with NK cells obtained from healthy donors, it was demonstrated that NK cells from cancer patients showed a significant reduction of both direct killing and ADCC against tumors, which was due to CD16 down-regulation [ 58 ]. In cancer patients, the expression levels of CD16, DNAM-1, and NKG2D have also been reported down-regulation on NK cells [ 59 , 60 ]. A Western blot assay using NK cells after stimulation with tumor cells may further add proof to possible CD16 shedding.…”