Fibroblast activation protein regulates natural killer cell migration, extravasation and tumor infiltration
Abstract Natural killer (NK) cells play a critical role in physiologic and pathologic conditions such as pregnancy, infection, autoimmune disease and cancer. In cancer, numerous strategies have been designed to exploit the cytolytic properties of NK cells, with variable success. A major hurdle to NK-cell focused therapies is NK cell recruitment and infiltration into tumors. While the chemotaxis pathways regulating NK recruitment to different tissues are well delineated, the mechanisms human NK cells employ to physically migrate are ill-defined. We show for the first time that human NK cells express fibroblast activation protein (FAP), a cell surface protease previously thought to be primarily expressed by activated fibroblasts. FAP degrades the extracellular matrix to facilitate cell migration and tissue remodeling. We used novelin vivozebrafish andin vitro3D culture models to demonstrate that FAP knock out and pharmacologic inhibition restrict NK cell migration, extravasation, and invasion through tissue matrix. Notably, forced overexpression of FAP promotes NK cell invasion through matrix in both transwell and tumor spheroid assays, ultimately increasing tumor cell lysis. Additionally, FAP overexpression enhances NK cells invasion into a human tumor in immunodeficient mice. These findings demonstrate the necessity of FAP in NK cell migration and present a new approach to modulate NK cell trafficking and enhance cell-based therapy in solid tumors.Graphical Abstract <jats:fig id="ufig1" position="float" orientation="portrait" fig-type="figure"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="429622v3_ufig1" position="float" orientation="portrait" /></jats:fig>.
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Preprint| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
bioRxiv.org - (2023) vom: 09. Dez. Zur Gesamtaufnahme - year:2023 |
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| Sprache: |
Englisch |
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| Beteiligte Personen: |
Fitzgerald, Allison A. [VerfasserIn] |
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| Links: |
Volltext [kostenfrei] |
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| doi: |
10.1101/2021.02.03.429622 |
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| PPN (Katalog-ID): |
XBI019877323 |
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| 100 | 1 | |a Fitzgerald, Allison A. |e verfasserin |0 (orcid)0000-0002-2814-0481 |4 aut | |
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| 520 | |a Abstract Natural killer (NK) cells play a critical role in physiologic and pathologic conditions such as pregnancy, infection, autoimmune disease and cancer. In cancer, numerous strategies have been designed to exploit the cytolytic properties of NK cells, with variable success. A major hurdle to NK-cell focused therapies is NK cell recruitment and infiltration into tumors. While the chemotaxis pathways regulating NK recruitment to different tissues are well delineated, the mechanisms human NK cells employ to physically migrate are ill-defined. We show for the first time that human NK cells express fibroblast activation protein (FAP), a cell surface protease previously thought to be primarily expressed by activated fibroblasts. FAP degrades the extracellular matrix to facilitate cell migration and tissue remodeling. We used novelin vivozebrafish andin vitro3D culture models to demonstrate that FAP knock out and pharmacologic inhibition restrict NK cell migration, extravasation, and invasion through tissue matrix. Notably, forced overexpression of FAP promotes NK cell invasion through matrix in both transwell and tumor spheroid assays, ultimately increasing tumor cell lysis. Additionally, FAP overexpression enhances NK cells invasion into a human tumor in immunodeficient mice. These findings demonstrate the necessity of FAP in NK cell migration and present a new approach to modulate NK cell trafficking and enhance cell-based therapy in solid tumors.Graphical Abstract <jats:fig id="ufig1" position="float" orientation="portrait" fig-type="figure"><jats:graphic xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="429622v3_ufig1" position="float" orientation="portrait" /></jats:fig> | ||
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| 700 | 1 | |a Marcisak, Emily F. |0 (orcid)0000-0001-8624-1013 |4 aut | |
| 700 | 1 | |a Nasir, Apsra |0 (orcid)0000-0003-3644-911X |4 aut | |
| 700 | 1 | |a Glasgow, Eric |0 (orcid)0000-0001-7729-3954 |4 aut | |
| 700 | 1 | |a Jablonski, Sandra A. |0 (orcid)0000-0001-7220-8159 |4 aut | |
| 700 | 1 | |a Van Der Veken, Pieter |0 (orcid)0000-0003-1208-3571 |4 aut | |
| 700 | 1 | |a Pearson, Gray |0 (orcid)0000-0001-6961-0227 |4 aut | |
| 700 | 1 | |a Eisman, Shira E. |4 aut | |
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| 700 | 1 | |a Fertig, Elana J. |0 (orcid)0000-0003-3204-342X |4 aut | |
| 700 | 1 | |a Weiner, Louis M. |0 (orcid)0000-0001-5192-0710 |4 aut | |
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