An Immunocompetent Microphysiological System to Simultaneously Investigate Effects of Anti-Tumor Natural Killer Cells on Tumor and Cardiac Microtissues
Existing first-line cancer therapies often fail to cope with the heterogeneity and complexity of cancers, so that new therapeutic approaches are urgently needed. Among novel alternative therapies, adoptive cell therapy (ACT) has emerged as a promising cancer treatment in recent years. The limited cl...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-12-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.781337/full |
| _version_ | 1818571105660567552 |
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| author | Oanh T. P. Nguyen Patrick M. Misun Christian Lohasz Jihyun Lee Weijia Wang Timm Schroeder Andreas Hierlemann |
| author_facet | Oanh T. P. Nguyen Patrick M. Misun Christian Lohasz Jihyun Lee Weijia Wang Timm Schroeder Andreas Hierlemann |
| author_sort | Oanh T. P. Nguyen |
| collection | DOAJ |
| description | Existing first-line cancer therapies often fail to cope with the heterogeneity and complexity of cancers, so that new therapeutic approaches are urgently needed. Among novel alternative therapies, adoptive cell therapy (ACT) has emerged as a promising cancer treatment in recent years. The limited clinical applications of ACT, despite its advantages over standard-of-care therapies, can be attributed to (i) time-consuming and cost-intensive procedures to screen for potent anti-tumor immune cells and the corresponding targets, (ii) difficulties to translate in-vitro and animal-derived in-vivo efficacies to clinical efficacy in humans, and (iii) the lack of systemic methods for the safety assessment of ACT. Suitable experimental models and testing platforms have the potential to accelerate the development of ACT. Immunocompetent microphysiological systems (iMPS) are microfluidic platforms that enable complex interactions of advanced tissue models with different immune cell types, bridging the gap between in-vitro and in-vivo studies. Here, we present a proof-of-concept iMPS that supports a triple culture of three-dimensional (3D) colorectal tumor microtissues, 3D cardiac microtissues, and human-derived natural killer (NK) cells in the same microfluidic network. Different aspects of tumor-NK cell interactions were characterized using this iMPS including: (i) direct interaction and NK cell-mediated tumor killing, (ii) the development of an inflammatory milieu through enrichment of soluble pro-inflammatory chemokines and cytokines, and (iii) secondary effects on healthy cardiac microtissues. We found a specific NK cell-mediated tumor-killing activity and elevated levels of tumor- and NK cell-derived chemokines and cytokines, indicating crosstalk and development of an inflammatory milieu. While viability and morphological integrity of cardiac microtissues remained mostly unaffected, we were able to detect alterations in their beating behavior, which shows the potential of iMPS for both, efficacy and early safety testing of new candidate ACTs. |
| first_indexed | 2024-12-14T13:51:11Z |
| format | Article |
| id | doaj.art-2df92aee5c0b4e4c80dccfbb7889809f |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-14T13:51:11Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-2df92aee5c0b4e4c80dccfbb7889809f2022-12-21T22:59:04ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-12-011210.3389/fimmu.2021.781337781337An Immunocompetent Microphysiological System to Simultaneously Investigate Effects of Anti-Tumor Natural Killer Cells on Tumor and Cardiac MicrotissuesOanh T. P. Nguyen0Patrick M. Misun1Christian Lohasz2Jihyun Lee3Weijia Wang4Timm Schroeder5Andreas Hierlemann6Bio Engineering Laboratory, Department of Biosystems Science and Engineering, ETH Zürich, Basel, SwitzerlandBio Engineering Laboratory, Department of Biosystems Science and Engineering, ETH Zürich, Basel, SwitzerlandBio Engineering Laboratory, Department of Biosystems Science and Engineering, ETH Zürich, Basel, SwitzerlandBio Engineering Laboratory, Department of Biosystems Science and Engineering, ETH Zürich, Basel, SwitzerlandCell Systems Dynamics Group, Department of Biosystems Science and Engineering, ETH Zürich, Basel, SwitzerlandCell Systems Dynamics Group, Department of Biosystems Science and Engineering, ETH Zürich, Basel, SwitzerlandBio Engineering Laboratory, Department of Biosystems Science and Engineering, ETH Zürich, Basel, SwitzerlandExisting first-line cancer therapies often fail to cope with the heterogeneity and complexity of cancers, so that new therapeutic approaches are urgently needed. Among novel alternative therapies, adoptive cell therapy (ACT) has emerged as a promising cancer treatment in recent years. The limited clinical applications of ACT, despite its advantages over standard-of-care therapies, can be attributed to (i) time-consuming and cost-intensive procedures to screen for potent anti-tumor immune cells and the corresponding targets, (ii) difficulties to translate in-vitro and animal-derived in-vivo efficacies to clinical efficacy in humans, and (iii) the lack of systemic methods for the safety assessment of ACT. Suitable experimental models and testing platforms have the potential to accelerate the development of ACT. Immunocompetent microphysiological systems (iMPS) are microfluidic platforms that enable complex interactions of advanced tissue models with different immune cell types, bridging the gap between in-vitro and in-vivo studies. Here, we present a proof-of-concept iMPS that supports a triple culture of three-dimensional (3D) colorectal tumor microtissues, 3D cardiac microtissues, and human-derived natural killer (NK) cells in the same microfluidic network. Different aspects of tumor-NK cell interactions were characterized using this iMPS including: (i) direct interaction and NK cell-mediated tumor killing, (ii) the development of an inflammatory milieu through enrichment of soluble pro-inflammatory chemokines and cytokines, and (iii) secondary effects on healthy cardiac microtissues. We found a specific NK cell-mediated tumor-killing activity and elevated levels of tumor- and NK cell-derived chemokines and cytokines, indicating crosstalk and development of an inflammatory milieu. While viability and morphological integrity of cardiac microtissues remained mostly unaffected, we were able to detect alterations in their beating behavior, which shows the potential of iMPS for both, efficacy and early safety testing of new candidate ACTs.https://www.frontiersin.org/articles/10.3389/fimmu.2021.781337/fullmicrophysiological system3D microtissuenatural killer celladoptive cell therapyefficacy and safety assessment |
| spellingShingle | Oanh T. P. Nguyen Patrick M. Misun Christian Lohasz Jihyun Lee Weijia Wang Timm Schroeder Andreas Hierlemann An Immunocompetent Microphysiological System to Simultaneously Investigate Effects of Anti-Tumor Natural Killer Cells on Tumor and Cardiac Microtissues Frontiers in Immunology microphysiological system 3D microtissue natural killer cell adoptive cell therapy efficacy and safety assessment |
| title | An Immunocompetent Microphysiological System to Simultaneously Investigate Effects of Anti-Tumor Natural Killer Cells on Tumor and Cardiac Microtissues |
| title_full | An Immunocompetent Microphysiological System to Simultaneously Investigate Effects of Anti-Tumor Natural Killer Cells on Tumor and Cardiac Microtissues |
| title_fullStr | An Immunocompetent Microphysiological System to Simultaneously Investigate Effects of Anti-Tumor Natural Killer Cells on Tumor and Cardiac Microtissues |
| title_full_unstemmed | An Immunocompetent Microphysiological System to Simultaneously Investigate Effects of Anti-Tumor Natural Killer Cells on Tumor and Cardiac Microtissues |
| title_short | An Immunocompetent Microphysiological System to Simultaneously Investigate Effects of Anti-Tumor Natural Killer Cells on Tumor and Cardiac Microtissues |
| title_sort | immunocompetent microphysiological system to simultaneously investigate effects of anti tumor natural killer cells on tumor and cardiac microtissues |
| topic | microphysiological system 3D microtissue natural killer cell adoptive cell therapy efficacy and safety assessment |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.781337/full |
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