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Intrinsic Functiona...
Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors
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- Oei, Vincent Yi Sheng (author)
- Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway.;Univ Oslo, Inst Clin Med, KG Jebsen Ctr Canc Immunotherapy, Oslo, Norway.
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- Siernicka, Marta (author)
- Med Univ Warsaw, Dept Immunol, Ctr Biostruct Res, Warsaw, Poland.;Med Univ Warsaw, Postgrad Sch Mol Med, Warsaw, Poland.
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- Graczyk-Jarzynka, Agnieszka (author)
- Med Univ Warsaw, Dept Immunol, Ctr Biostruct Res, Warsaw, Poland.
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- Hoel, Hanna Julie (author)
- Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway.
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- Yang, Weiwen (author)
- Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway.
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- Palacios, Daniel (author)
- Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway.;Univ Oslo, Inst Clin Med, KG Jebsen Ctr Canc Immunotherapy, Oslo, Norway.
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- Almasbak, Hilde (author)
- Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway.
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- Bajor, Malgorzata (author)
- Med Univ Warsaw, Dept Immunol, Ctr Biostruct Res, Warsaw, Poland.
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- Clement, Dennis (author)
- Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway.;Univ Oslo, Inst Clin Med, KG Jebsen Ctr Canc Immunotherapy, Oslo, Norway.
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- Brandt, Ludwig (author)
- KTH,Science for Life Laboratory, SciLifeLab
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- Önfelt, Björn (author)
- Karolinska Institutet,KTH,Tillämpad fysik,Science for Life Laboratory, SciLifeLab,Karolinska Inst
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- Goodridge, Jodie (author)
- Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway.;Univ Oslo, Inst Clin Med, KG Jebsen Ctr Canc Immunotherapy, Oslo, Norway.
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- Winiarska, Magdalena (author)
- Med Univ Warsaw, Dept Immunol, Ctr Biostruct Res, Warsaw, Poland.
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- Zagozdzon, Radoslaw (author)
- Med Univ Warsaw, Dept Immunol, Ctr Biostruct Res, Warsaw, Poland.;Med Univ Warsaw, Inst Transplantat, Dept Clin Immunol, Warsaw, Poland.
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- Olweus, Johanna (author)
- Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway.;Univ Oslo, Inst Clin Med, KG Jebsen Ctr Canc Immunotherapy, Oslo, Norway.
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- Kyte, Jon-Amund (author)
- Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway.;Oslo Univ Hosp, Dept Oncol, Oslo, Norway.
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- Malmberg, Karl-Johan (author)
- Karolinska Institutet
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Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway;Univ Oslo, Inst Clin Med, KG Jebsen Ctr Canc Immunotherapy, Oslo, Norway. Med Univ Warsaw, Dept Immunol, Ctr Biostruct Res, Warsaw, Poland.;Med Univ Warsaw, Postgrad Sch Mol Med, Warsaw, Poland. (creator_code:org_t)
- AMER ASSOC CANCER RESEARCH, 2018
- 2018
- English.
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In: CANCER IMMUNOLOGY RESEARCH. - : AMER ASSOC CANCER RESEARCH. - 2326-6066 .- 2326-6074. ; 6:4, s. 467-480
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- Natural killer (NK) cells hold potential as a source of allogeneic cytotoxic effector cells for chimeric antigen receptor (CAR)-mediated therapies. Here, we explored the feasibility of transfecting CAR-encoding mRNA into primary NK cells and investigated how the intrinsic potential of discrete NK-cell subsets affects retargeting efficiency. After screening five second- and third-generation anti-CD19 CAR constructs with different signaling domains and spacer regions, a third-generation CAR with the CH2-domain removed was selected based on its expression and functional profiles. Kinetics experiments revealed that CAR expression was optimal after 3 days of IL15 stimulation prior to transfection, consistently achieving over 80% expression. CAR-engineered NK cells acquired increased degranulation toward CD19(+) targets, and maintained their intrinsic degranulation response toward CD19(-) K562 cells. The response of redirected NK-cell subsets against CD19(+) targets was dependent on their intrinsic thresholds for activation determined through both differentiation and education by killer cell immunoglobulin-like receptors (KIR) and/or CD94/NKG2A binding to self HLA class I and HLA-E, respectively. Redirected primary NK cells were insensitive to inhibition through NKG2A/HLA-E interactions but remained sensitive to inhibition through KIR depending on the amount of HLA class I expressed on target cells. Adaptive NK cells, expressing NKG2C, CD57, and self-HLA-specific KIR(s), displayed superior ability to kill CD19(+), HLA low, or mismatched tumor cells. These findings support the feasibility of primary allogeneic NK cells for CAR engineering and highlight a need to consider NK-cell diversity when optimizing efficacy of cancer immunotherapies based on CAR-expressing NK cells.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Oei, Vincent Yi ...
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Siernicka, Marta
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Graczyk-Jarzynka ...
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Hoel, Hanna Juli ...
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Yang, Weiwen
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Palacios, Daniel
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show more...
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Almasbak, Hilde
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Bajor, Malgorzat ...
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Clement, Dennis
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Brandt, Ludwig
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Önfelt, Björn
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Goodridge, Jodie
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Winiarska, Magda ...
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Zagozdzon, Rados ...
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Olweus, Johanna
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Kyte, Jon-Amund
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Malmberg, Karl-J ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Cell and Molecul ...
- Articles in the publication
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CANCER IMMUNOLOG ...
- By the university
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Royal Institute of Technology
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Karolinska Institutet