Natural killer cells activity against multiple myeloma cells is modulated by osteoblast-induced IL-6 and IL-10 production

被引:6
作者
Uhl, Christopher [1 ]
Nyirenda, Themba [2 ]
Siegel, David S. [1 ,2 ]
Lee, Woo Y. [3 ]
Zilberberg, Jenny [1 ]
机构
[1] Ctr Discovery & Innovat, 111 Ideation Way,Bldg 102, Nutley, NJ 07110 USA
[2] John Theurer Canc Ctr, 92 2nd St Ste 301, Hackensack, NJ 07601 USA
[3] Stevens Inst Technol, Dept Chem & Chem Biol, 1 Castle Point Hudson, Hoboken, NJ 07030 USA
基金
美国国家卫生研究院;
关键词
NK cells; Multiple myeloma; Cytotoxicity; Osteoblasts; Microenvironment; MEDIATED DRUG-RESISTANCE; TUMOR MICROENVIRONMENT; EXTRACELLULAR-MATRIX; NK CELLS; THERAPY; MODEL; NK-92; LINE;
D O I
10.1016/j.heliyon.2022.e09167
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Background: Natural killer (NK) cells are part of the innate arm of the immune system; as such NK cells can be activated rapidly to target virus-infected cells and tumor cells without prior sensitization. The human NK-92MI cell line is among the most widely used NK cell in preclinical research studies and has also been approved for clinical applications. Previous studies have shown that osteoblasts (OSB) confer drug resistance in multiple myeloma (MM) and other cancers that metastasize to the bone marrow. Aim: We evaluated here how OSB, which are bone forming cells and a key cellular component of the bone marrow microenvironment, modulate the cytotoxic activity of NK-92MI cells against the MM.1S multiple myeloma cell line. Methods: The osteoblastic niche was recapitulated with either the osteoblastic cell line hFOB 1.19 (hFOB) or primary osteoblasts (P-OSB) derived from surgical resections. Time-lapse imaging was utilized to quantify changes in MM.1S cell viability under different conditions, including: (1) Co-culture of MM.1S with NK92MI cells, (2) triple-culture of hFOB or P-OSB with MM.1S and NK-92MI, and (3) MM.1S or NK-92MI cells primed with OSB-derived supernatant. Cytokine analysis was conducted to quantify potential secreted factors associated with the protective effects of OSB. Results: The physical presence of OSB hindered the activity of NK-92MI cells, resulting in the increased viability of MM.1S compared to co-cultures which lacked OSB. This observation was accompanied by reduced perforin and granzyme A secretion from NK-92MI cells. Contact of OSB and NK-92MI cells also induced interleukin 6 (IL-6) and interleukin 10 (IL-10) production; two cytokines which are known to impair the NK cell immunity against MM and other cancers. OSB supernatant also conferred cytoprotection to MM.1S, suggesting a dual mechanism by which OSB may modulate both NK and MM cells. Conclusions: We demonstrated here that OSB can negatively impact the activity of NK cells against MM. As NK cells and their chimeric antigen receptor-modified versions become more widely used in the clinic, our results suggest that understanding the role of OSB as potential immunoregulators of the NK cell-mediated cytotoxic response in the bone marrow tumor microenvironment may provide new opportunities for enhancing the effectiveness of this potent immunotherapeutic approach.
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页数:8
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