Natural killer cells activity against multiple myeloma cells is modulated by osteoblast-induced IL-6 and IL-10 production
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 studi...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-03-01
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| Series: | Heliyon |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2405844022004558 |
| _version_ | 1818775429038735360 |
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| author | Christopher Uhl Themba Nyirenda David S. Siegel Woo Y. Lee Jenny Zilberberg |
| author_facet | Christopher Uhl Themba Nyirenda David S. Siegel Woo Y. Lee Jenny Zilberberg |
| author_sort | Christopher Uhl |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-18T10:56:53Z |
| format | Article |
| id | doaj.art-3ef5abb2659a4ceb98e4db0a28a09cd5 |
| institution | Directory Open Access Journal |
| issn | 2405-8440 |
| language | English |
| last_indexed | 2024-12-18T10:56:53Z |
| publishDate | 2022-03-01 |
| publisher | Elsevier |
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| series | Heliyon |
| spelling | doaj.art-3ef5abb2659a4ceb98e4db0a28a09cd52022-12-21T21:10:18ZengElsevierHeliyon2405-84402022-03-0183e09167Natural killer cells activity against multiple myeloma cells is modulated by osteoblast-induced IL-6 and IL-10 productionChristopher Uhl0Themba Nyirenda1David S. Siegel2Woo Y. Lee3Jenny Zilberberg4Center for Discovery and Innovation, 111 Ideation Way, Building 102, Nutley, NJ 07110, USAJohn Theurer Cancer Center, 92 2nd St Ste 301 Hackensack, NJ 07601, USACenter for Discovery and Innovation, 111 Ideation Way, Building 102, Nutley, NJ 07110, USA; John Theurer Cancer Center, 92 2nd St Ste 301 Hackensack, NJ 07601, USADepartment of Chemistry and Chemical Biology, Stevens Institute of Technology, 1 Castle Point on Hudson, Hoboken, NJ, 07030, USACenter for Discovery and Innovation, 111 Ideation Way, Building 102, Nutley, NJ 07110, USA; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2405844022004558NK cellsMultiple myelomaCytotoxicityOsteoblastsMicroenvironment |
| spellingShingle | Christopher Uhl Themba Nyirenda David S. Siegel Woo Y. Lee Jenny Zilberberg Natural killer cells activity against multiple myeloma cells is modulated by osteoblast-induced IL-6 and IL-10 production Heliyon NK cells Multiple myeloma Cytotoxicity Osteoblasts Microenvironment |
| title | Natural killer cells activity against multiple myeloma cells is modulated by osteoblast-induced IL-6 and IL-10 production |
| title_full | Natural killer cells activity against multiple myeloma cells is modulated by osteoblast-induced IL-6 and IL-10 production |
| title_fullStr | Natural killer cells activity against multiple myeloma cells is modulated by osteoblast-induced IL-6 and IL-10 production |
| title_full_unstemmed | Natural killer cells activity against multiple myeloma cells is modulated by osteoblast-induced IL-6 and IL-10 production |
| title_short | Natural killer cells activity against multiple myeloma cells is modulated by osteoblast-induced IL-6 and IL-10 production |
| title_sort | natural killer cells activity against multiple myeloma cells is modulated by osteoblast induced il 6 and il 10 production |
| topic | NK cells Multiple myeloma Cytotoxicity Osteoblasts Microenvironment |
| url | http://www.sciencedirect.com/science/article/pii/S2405844022004558 |
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