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Updated: Jul 6, 2025
Flow Cytometry-based Assay for the Monitoring of NK Cell Functions
Published on: October 30, 2016
Clearing soluble MIC reverses the impaired function of natural killer cells from patients with multiple myeloma
Sojeong Kim1, Haerim Chung1, Jeong-Eun Kwak1
1Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of).
Background:
Major histocompatibility complex (MHC) class I chain-related protein (MIC) is a stress-induced ligand released from multiple myeloma (MM) cells during progression, and soluble MIC impairs natural killer group 2D (NKG2D) activating receptor-mediated recognition and function of natural killer (NK) cells. However, whether clearing soluble MIC with a monoclonal antibody (mAb) can restore NK cell activity of MM patients remains undetermined.
Methods:
We analyzed The Cancer Genome Atlas (TCGA) Multiple Myeloma Research Foundation (MMRF) CoMMpass data set to examine the prognostic significance of MIC expression in MM. We examined the level of soluble MIC in paired peripheral blood (PB) and bone marrow (BM) plasma of patients with MM at diagnosis by ELISA. We evaluated the correlation between the level of soluble MIC and immunophenotype of NK cells from MM patients by multicolor flow cytometry. We also generated MIC-overexpressing MM cell line and characterized the cytotoxic function of patient NK cells in the presence of soluble MIC, and examined the impact of clearing soluble MIC with a humanized mAb (huB10G5).
Results:
We characterize the importance of MICA in MM by revealing the significantly better overall survival of patients with high MICA expression from TCGA MMRF CoMMpass data set. The level of soluble MICA is more highly elevated in MM than in precursor stages, and the concentration of soluble MICA is higher in BM plasma than in PB. The concentration of soluble MICA in BM was correlated with myeloma burden, while it was negatively correlated with the frequency of NKG2D+ NK cells in diagnostic BM aspirates of MM patients. Soluble MICA downregulated NKG2D expression and decreased cytotoxicity of MM patient NK cells ex vivo, which were reversed by a humanized soluble MIC-clearing mAb (huB10G5) with enhanced degranulation of NK cells.
Conclusions:
Our findings indicate targeting soluble MIC with huB10G5 might be a viable therapeutic approach to promote NKG2D-dependent cellular immunotherapy outcome in MM.
Insights
Targeting soluble Major histocompatibility complex (MHC) class I chain-related protein (MIC) with a humanized antibody (huB10G5) may restore natural killer (NK) cell activity in multiple myeloma (MM) patients. This approach shows promise for enhancing cellular immunotherapy outcomes in MM.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Major histocompatibility complex (MHC) class I chain-related protein (MIC) is a stress-induced ligand released by multiple myeloma (MM) cells.
- Soluble MIC impairs natural killer (NK) cell recognition and function by inhibiting the NKG2D receptor.
- The efficacy of clearing soluble MIC to restore NK cell activity in MM patients is not well-established.
Purpose of the Study:
- To investigate the prognostic significance of MIC expression in MM using TCGA MMRF CoMMpass data.
- To analyze soluble MIC levels in MM patients and their correlation with NK cell immunophenotype.
- To evaluate the therapeutic potential of clearing soluble MIC with a monoclonal antibody (mAb) in MM.
Main Methods:
- Analysis of TCGA MMRF CoMMpass data for MIC expression and overall survival.
- ELISA to measure soluble MIC levels in peripheral blood and bone marrow plasma.
- Multicolor flow cytometry to assess NK cell immunophenotype and NKG2D expression.
- Functional assays to evaluate NK cell cytotoxicity against MIC-overexpressing MM cells and the effect of huB10G5.
Main Results:
- High MICA expression is associated with significantly better overall survival in MM patients.
- Soluble MICA levels are elevated in MM, higher in bone marrow than peripheral blood, and correlate with myeloma burden.
- Soluble MICA downregulates NKG2D expression and reduces NK cell cytotoxicity, which is reversed by huB10G5, enhancing NK cell degranulation.
Conclusions:
- Targeting soluble MIC with huB10G5 represents a potential therapeutic strategy for MM.
- Clearing soluble MIC may restore NK cell function and improve outcomes in NKG2D-dependent cellular immunotherapy for MM.
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