Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Intrinsic Functional Potential of NK-Cell Subsets Constrains Retargeting Driven by Chimeric Antigen Receptors
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..
Med Univ Warsaw, Dept Immunol, Ctr Biostruct Res, Warsaw, Poland..
Radiumhospitalet, Oslo Univ Hosp, Inst Canc Res, Dept Canc Immunol, Oslo, Norway..
Show others and affiliations
2018 (English)In: CANCER IMMUNOLOGY RESEARCH, ISSN 2326-6066, Vol. 6, no 4, p. 467-480Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH , 2018. Vol. 6, no 4, p. 467-480
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:kth:diva-228141DOI: 10.1158/2326-6066.CIR-17-0207ISI: 000429044000010PubMedID: 29459477OAI: oai:DiVA.org:kth-228141DiVA, id: diva2:1207037
Note

QC 20180518

Available from: 2018-05-18 Created: 2018-05-18 Last updated: 2018-05-18Bibliographically approved

Open Access in DiVA

No full text in DiVA

Other links

Publisher's full textPubMed

Authority records BETA

Brandt, LudwigÖnfelt, Björn

Search in DiVA

By author/editor
Brandt, LudwigÖnfelt, Björn
By organisation
Science for Life Laboratory, SciLifeLabApplied Physics
Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar

doi
pubmed
urn-nbn

Altmetric score

doi
pubmed
urn-nbn
Total: 8 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf