serval:BIB_799B70627D11
CART cells are prone to Fas- and DR5-mediated cell death.
10.1186/s40425-018-0385-z
000438502800002
30005714
Tschumi
B.O.
author
Dumauthioz
N.
author
Marti
B.
author
Zhang
L.
author
Lanitis
E.
author
Irving
M.
author
Schneider
P.
author
Mach
J.P.
author
Coukos
George
author
Romero
P.
author
Donda
A.
author
article
2018-07-13
Journal for immunotherapy of cancer
2051-1426
2051-1426
journal
6
1
71
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.
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
eng
60_published
true
peer-reviewed
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: epublish
University of Lausanne
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