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Complementarity-det...
Complementarity-determining region clustering may cause CAR-T cell dysfunction
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- Sarén, Tina (author)
- Uppsala universitet,Cancerimmunterapi,Science for Life Laboratory, SciLifeLab
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- Saronio, Giulia (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab
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- Marti Torrell, Paula (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab
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- Zhu, Xu (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab
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- Thelander, Josefin (author)
- Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab
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- Andersson, Yasmin (author)
- KTH,Läkemedelsutveckling,Science for Life Laboratory, SciLifeLab,Royal Inst Technol KTH, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden.
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- Hofström, Camilla (author)
- KTH,Läkemedelsutveckling,Science for Life Laboratory, SciLifeLab,Royal Inst Technol KTH, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden.
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- Nestor, Marika, 1976- (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerprecisionsmedicin
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- Dimberg, Anna (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Vaskulärbiologi
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- Persson, Helena (author)
- KTH,Läkemedelsutveckling,Science for Life Laboratory, SciLifeLab,Royal Inst Technol KTH, Sci Life Lab, Drug Discovery & Dev Platform, Solna, Sweden.
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- Ramachandran, Mohanraj, 1988- (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerimmunterapi,Vaskulärbiologi
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- Yu, Di, 1985- (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerimmunterapi
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- Essand, Magnus (author)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Cancerimmunterapi
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(creator_code:org_t)
- Springer Nature, 2023
- 2023
- English.
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In: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1, s. 4732-
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https://doi.org/10.1...
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https://uu.diva-port... (primary) (Raw object)
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Abstract
Subject headings
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- Chimeric antigen receptor (CAR)-T cell therapy is rapidly advancing as cancer treatment, however, designing an optimal CAR remains challenging. A single-chain variable fragment (scFv) is generally used as CAR targeting moiety, wherein the complementarity-determining regions (CDRs) define its specificity. We report here that the CDR loops can cause CAR clustering, leading to antigen-independent tonic signalling and subsequent CAR-T cell dysfunction. We show via CARs incorporating scFvs with identical framework and varying CDR sequences that CARs may cluster on the T cell surface, which leads to antigen-independent CAR-T cell activation, characterized by increased cell size and interferon (IFN)-γ secretion. This results in CAR-T cell exhaustion, activation-induced cell death and reduced responsiveness to target-antigen-expressing tumour cells. CDR mutagenesis confirms that the CAR-clustering is mediated by CDR-loops. In summary, antigen-independent tonic signalling can be induced by CDR-mediated CAR clustering, which could not be predicted from the scFv sequences, but could be tested for by evaluating the activity of unstimulated CAR-T cells.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Sarén, Tina
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Saronio, Giulia
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Marti Torrell, P ...
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Zhu, Xu
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Thelander, Josef ...
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Andersson, Yasmi ...
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Hofström, Camill ...
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Nestor, Marika, ...
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Dimberg, Anna
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Persson, Helena
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Ramachandran, Mo ...
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Yu, Di, 1985-
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Essand, Magnus
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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 Immunology in th ...
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Nature Communica ...
- By the university
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Royal Institute of Technology
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Uppsala University