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

SIMPLE SUMMARY: Multiple myeloma (MM) is a deadly cancer localized in the bone marrow, where changes can support progression and therapy resistance. This study examined the expression of numerous biological markers on natural killer (NK) cells in blood and bone marrow of patients with MM. NK cells play key roles in the innate immunosurveillance of MM, so we sought to identify biomarkers on NK cells that may be prognostic for patient outcomes and identify new therapeutic targets in these patients. Biomarker expression was compared on NK cells between MM disease stages and healthy donors, between blood and bone marrow, and associations with disease progression. The study shows that loss of certain biomarkers on NK cells may limit their anti-tumor function in MM patients, that several drug-targetable biomarkers are upregulated on NK cells, and that high expression of the biomarker, SLAMF7, may have prognostic potential to identify patients more likely to show rapid disease progression. 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 CD56(dim) 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.