CART cells are prone to Fas- and DR5-mediated cell death.

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Version: Final published version
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Serval ID
serval:BIB_799B70627D11
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
CART cells are prone to Fas- and DR5-mediated cell death.
Journal
Journal for immunotherapy of cancer
Author(s)
Tschumi B.O., Dumauthioz N., Marti B., Zhang L., Lanitis E., Irving M., Schneider P., Mach J.P., Coukos George, Romero P., Donda A.
ISSN
2051-1426 (Electronic)
ISSN-L
2051-1426
Publication state
Published
Issued date
13/07/2018
Peer-reviewed
Oui
Volume
6
Number
1
Pages
71
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
Abstract
Adoptive transfer of T cells transduced with Chimeric Antigen Receptors (CAR) are now FDA-approved for the treatment of B-cell malignancies. Yet, the functionality of the endogenous TCR in CART cells has not been fully assessed. Here, we demonstrate that CART cells progressively upregulate Fas, FasL, DR5 and TRAIL, which result in their programmed cell death, independently of antigen-mediated TCR or CAR activation. CART cell apoptosis occurs even when the CAR contains a single (co-)activatory domain such as CD3ζ, CD28 or 4-1BB. Importantly, the dominant role of the Fas and DR5 pathways in CART cell apoptosis is demonstrated by the significant rescue of CART cells upon in vivo blockade by combined Fas-Fc and DR5-Fc recombinant proteins. These observations are of crucial importance for the long-term persistence of CART cells and for the development of new applications including the combined TCR and CAR activation against solid tumors.
Keywords
Animals, Cell Death, Fas Ligand Protein/immunology, Female, Immunotherapy, Adoptive, Melanoma, Experimental/pathology, Melanoma, Experimental/therapy, Mice, Inbred C57BL, Receptors, Chimeric Antigen/immunology, Receptors, TNF-Related Apoptosis-Inducing Ligand/immunology, Skin Neoplasms/pathology, Skin Neoplasms/therapy, TNF-Related Apoptosis-Inducing Ligand/immunology, Tumor Burden, fas Receptor/immunology, 4-1BB, Annexin V, CAR T cells, CD28, CD3ζ, CD8 T lymphocytes, Fas, FasL, HER2, Listeria monocytogenes
Pubmed
Web of science
Open Access
Yes
Create date
06/08/2018 8:40
Last modification date
07/02/2020 6:19
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