Clearing soluble MIC reverses the impaired function of natural killer cells from patients with multiple myeloma.

Autor:	Kim S; Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)., Chung H; Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)., Kwak JE; Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)., Kim YR; Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)., Park CH; Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)., Kim Y; Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)., Cheong JW; Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of)., Wu J; Department of Urology and Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA., Shin EC; Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea (the Republic of) hyunsoocho@yuhs.ac hemakim@yuhs.ac ecshin@kaist.ac.kr., Cho H; Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of) hyunsoocho@yuhs.ac hemakim@yuhs.ac ecshin@kaist.ac.kr., Kim JS; Division of Hematology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea (the Republic of) hyunsoocho@yuhs.ac hemakim@yuhs.ac ecshin@kaist.ac.kr.
Jazyk:	angličtina
Zdroj:	Journal for immunotherapy of cancer [J Immunother Cancer] 2024 Jan 08; Vol. 12 (1). Date of Electronic Publication: 2024 Jan 08.
DOI:	10.1136/jitc-2023-007886
Abstrakt:	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. Competing Interests: Competing interests: JW is the inventor of the huB10G5 antibody with international patents and the remaining authors declare no potential conflicts of interest. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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