Cryopreserved Human Natural Killer Cells Exhibit Potent Antitumor Efficacy against Orthotopic Pancreatic Cancer through Efficient Tumor-Homing and Cytolytic Ability (Running Title: Cryopreserved NK Cells Exhibit Antitumor Effect)
Pancreatic cancer is known to be highly aggressive, and desmoplasia-induced accumulation of extracellular matrix (ECM), which is a hallmark of many pancreatic cancers, severely restricts the therapeutic efficacy of both immunotherapeutics and conventional chemotherapeutics due to the ECM functioning...
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MDPI AG
2019-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/7/966 |
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| author | Eonju Oh Bokyung Min Yan Li ChunYing Lian JinWoo Hong Gyeong-min Park Bitna Yang Sung Yoo Cho Yu Kyeong Hwang Chae-Ok Yun |
| author_facet | Eonju Oh Bokyung Min Yan Li ChunYing Lian JinWoo Hong Gyeong-min Park Bitna Yang Sung Yoo Cho Yu Kyeong Hwang Chae-Ok Yun |
| author_sort | Eonju Oh |
| collection | DOAJ |
| description | Pancreatic cancer is known to be highly aggressive, and desmoplasia-induced accumulation of extracellular matrix (ECM), which is a hallmark of many pancreatic cancers, severely restricts the therapeutic efficacy of both immunotherapeutics and conventional chemotherapeutics due to the ECM functioning as a major physical barrier against permeation and penetration. In the case of cell-based immunotherapeutics, there are several other bottlenecks preventing translation into clinical use due to their biological nature; for example, poor availability of cell therapeutic in a readily usable form due to difficulties in production, handling, shipping, and storage. To address these challenges, we have isolated allogeneic natural killer (NK) cells from healthy donors and expanded them <i>in vitro</i> to generate cryopreserved stocks. These cryopreserved NK cells were thawed to evaluate their therapeutic efficacy against desmoplastic pancreatic tumors, ultimately aiming to develop a readily accessible and mass-producible off-the-shelf cell-based immunotherapeutic. The cultured NK cells post-thawing retained highly pure populations of activated NK cells that expressed various activating receptors and a chemokine receptor. Furthermore, systemic administration of NK cells induced greater <i>in vivo</i> tumor growth suppression when compared with gemcitabine, which is the standard chemotherapeutic used for pancreatic cancer treatment. The potent antitumor effect of NK cells was mediated by efficient tumor-homing ability and infiltration into desmoplastic tumor tissues. Moreover, the infiltration of NK cells led to strong induction of apoptosis, elevated expression of the antitumor cytokine interferon (IFN)-γ, and inhibited expression of the immunosuppressive transforming growth factor (TGF)-β in tumor tissues. Expanded and cryopreserved NK cells are strong candidates for future cell-mediated systemic immunotherapy against pancreatic cancer. |
| first_indexed | 2024-03-12T07:36:49Z |
| format | Article |
| id | doaj.art-dcfc4301961241e2950d3f3b45fe88d4 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T07:36:49Z |
| publishDate | 2019-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-dcfc4301961241e2950d3f3b45fe88d42023-09-02T21:29:22ZengMDPI AGCancers2072-66942019-07-0111796610.3390/cancers11070966cancers11070966Cryopreserved Human Natural Killer Cells Exhibit Potent Antitumor Efficacy against Orthotopic Pancreatic Cancer through Efficient Tumor-Homing and Cytolytic Ability (Running Title: Cryopreserved NK Cells Exhibit Antitumor Effect)Eonju Oh0Bokyung Min1Yan Li2ChunYing Lian3JinWoo Hong4Gyeong-min Park5Bitna Yang6Sung Yoo Cho7Yu Kyeong Hwang8Chae-Ok Yun9Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, KoreaGC LabCell 107, Ihyeon-ro 30beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 16924, KoreaDepartment of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, KoreaDepartment of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, KoreaDepartment of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, KoreaGC LabCell 107, Ihyeon-ro 30beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 16924, KoreaGC LabCell 107, Ihyeon-ro 30beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 16924, KoreaGC LabCell 107, Ihyeon-ro 30beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 16924, KoreaGC LabCell 107, Ihyeon-ro 30beon-gil, Giheung-gu, Yongin-si, Gyeonggi-do 16924, KoreaDepartment of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul 04763, KoreaPancreatic cancer is known to be highly aggressive, and desmoplasia-induced accumulation of extracellular matrix (ECM), which is a hallmark of many pancreatic cancers, severely restricts the therapeutic efficacy of both immunotherapeutics and conventional chemotherapeutics due to the ECM functioning as a major physical barrier against permeation and penetration. In the case of cell-based immunotherapeutics, there are several other bottlenecks preventing translation into clinical use due to their biological nature; for example, poor availability of cell therapeutic in a readily usable form due to difficulties in production, handling, shipping, and storage. To address these challenges, we have isolated allogeneic natural killer (NK) cells from healthy donors and expanded them <i>in vitro</i> to generate cryopreserved stocks. These cryopreserved NK cells were thawed to evaluate their therapeutic efficacy against desmoplastic pancreatic tumors, ultimately aiming to develop a readily accessible and mass-producible off-the-shelf cell-based immunotherapeutic. The cultured NK cells post-thawing retained highly pure populations of activated NK cells that expressed various activating receptors and a chemokine receptor. Furthermore, systemic administration of NK cells induced greater <i>in vivo</i> tumor growth suppression when compared with gemcitabine, which is the standard chemotherapeutic used for pancreatic cancer treatment. The potent antitumor effect of NK cells was mediated by efficient tumor-homing ability and infiltration into desmoplastic tumor tissues. Moreover, the infiltration of NK cells led to strong induction of apoptosis, elevated expression of the antitumor cytokine interferon (IFN)-γ, and inhibited expression of the immunosuppressive transforming growth factor (TGF)-β in tumor tissues. Expanded and cryopreserved NK cells are strong candidates for future cell-mediated systemic immunotherapy against pancreatic cancer.https://www.mdpi.com/2072-6694/11/7/966adoptive cell therapyallogeneic natural killer cellscancer immunologypancreatic cancerapoptosis |
| spellingShingle | Eonju Oh Bokyung Min Yan Li ChunYing Lian JinWoo Hong Gyeong-min Park Bitna Yang Sung Yoo Cho Yu Kyeong Hwang Chae-Ok Yun Cryopreserved Human Natural Killer Cells Exhibit Potent Antitumor Efficacy against Orthotopic Pancreatic Cancer through Efficient Tumor-Homing and Cytolytic Ability (Running Title: Cryopreserved NK Cells Exhibit Antitumor Effect) Cancers adoptive cell therapy allogeneic natural killer cells cancer immunology pancreatic cancer apoptosis |
| title | Cryopreserved Human Natural Killer Cells Exhibit Potent Antitumor Efficacy against Orthotopic Pancreatic Cancer through Efficient Tumor-Homing and Cytolytic Ability (Running Title: Cryopreserved NK Cells Exhibit Antitumor Effect) |
| title_full | Cryopreserved Human Natural Killer Cells Exhibit Potent Antitumor Efficacy against Orthotopic Pancreatic Cancer through Efficient Tumor-Homing and Cytolytic Ability (Running Title: Cryopreserved NK Cells Exhibit Antitumor Effect) |
| title_fullStr | Cryopreserved Human Natural Killer Cells Exhibit Potent Antitumor Efficacy against Orthotopic Pancreatic Cancer through Efficient Tumor-Homing and Cytolytic Ability (Running Title: Cryopreserved NK Cells Exhibit Antitumor Effect) |
| title_full_unstemmed | Cryopreserved Human Natural Killer Cells Exhibit Potent Antitumor Efficacy against Orthotopic Pancreatic Cancer through Efficient Tumor-Homing and Cytolytic Ability (Running Title: Cryopreserved NK Cells Exhibit Antitumor Effect) |
| title_short | Cryopreserved Human Natural Killer Cells Exhibit Potent Antitumor Efficacy against Orthotopic Pancreatic Cancer through Efficient Tumor-Homing and Cytolytic Ability (Running Title: Cryopreserved NK Cells Exhibit Antitumor Effect) |
| title_sort | cryopreserved human natural killer cells exhibit potent antitumor efficacy against orthotopic pancreatic cancer through efficient tumor homing and cytolytic ability running title cryopreserved nk cells exhibit antitumor effect |
| topic | adoptive cell therapy allogeneic natural killer cells cancer immunology pancreatic cancer apoptosis |
| url | https://www.mdpi.com/2072-6694/11/7/966 |
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