RT Journal Article
SR Electronic
T1 CART cells are prone to Fas- and DR5-mediated cell death
JF Journal for ImmunoTherapy of Cancer
JO J Immunother Cancer
FD BMJ Publishing Group Ltd
SP 71
DO 10.1186/s40425-018-0385-z
VO 6
IS 1
A1 Tschumi, Benjamin O.
A1 Dumauthioz, Nina
A1 Marti, Bastien
A1 Zhang, Lianjun
A1 Schneider, Pascal
A1 Mach, Jean-Pierre
A1 Romero, Pedro
A1 Donda, Alena
YR 2018
UL http://jitc.bmj.com/content/6/1/71.abstract
AB 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.A correction to this article is available online at https://doi.org/10.1186/s40425-018-0410-2.Abbreviations:ACTAdoptive Cell TransferAICDActivation Induced Cell DeathBFPBlue Fluorescent ProteinCARTChimeric antigen receptor-transduced T cellsCEACarcinoembryonic antigen 2GvHDGraft-versus-host diseaseHER2Human epidermal growth factor receptorPCDProgrammed Cell DeathrLm-OVArecombinant Listeria monocytogenes expressing OVA134–387TCRT cell-receptor