Functional Tuning of CARs Reveals Signaling Threshold above Which CD8+ CTL Antitumor Potency Is Attenuated due to Cell Fas-FasL-Dependent AICD

Chimeric antigen receptor (CAR) development is biased toward selecting constructs that elicit the highest magnitude of T-cell functional outputs. Here, we show that components of CAR extracellular spacer and cytoplasmic signaling domain modulate, in a cooperative manner, the magnitude of CD8(+)CTL a...

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Bibliographic Details
Published inCancer immunology research Vol. 3; no. 4; p. 368
Main Authors Künkele, Annette, Johnson, Adam J, Rolczynski, Lisa S, Chang, Cindy A, Hoglund, Virginia, Kelly-Spratt, Karen S, Jensen, Michael C
Format Journal Article
LanguageEnglish
Published United States 01.04.2015
Subjects
Animals
Brain Neoplasms - immunology
Brain Neoplasms - therapy
Cell Line, Tumor
Cytotoxicity, Immunologic - immunology
Fas Ligand Protein - immunology
fas Receptor - immunology
Genetic Vectors
Humans
Lentivirus - genetics
Lymphocyte Activation - immunology
Mice, Inbred NOD
Mice, SCID
Neuroblastoma - immunology
Neuroblastoma - therapy
Receptors, Antigen, T-Cell - genetics
Receptors, Antigen, T-Cell - immunology
Recombinant Fusion Proteins - immunology
Signal Transduction - immunology
T-Lymphocytes, Cytotoxic - immunology
Xenograft Model Antitumor Assays
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Summary:Chimeric antigen receptor (CAR) development is biased toward selecting constructs that elicit the highest magnitude of T-cell functional outputs. Here, we show that components of CAR extracellular spacer and cytoplasmic signaling domain modulate, in a cooperative manner, the magnitude of CD8(+)CTL activation for tumor-cell cytolysis and cytokine secretion. Unexpectedly, CAR constructs that generate the highest in vitro activity, either by extracellular spacer length tuning or by the addition of cytoplasmic signaling modules, exhibit attenuated antitumor potency in vivo, whereas CARs tuned for moderate signaling outputs mediate tumor eradication. Recursive CAR triggering renders CTLs expressing hyperactive CARs highly susceptible to activation-induced cell death (AICD) as a result of augmented FasL expression. CAR tuning using combinations of extracellular spacers and cytoplasmic signaling modules, which limit AICD of CD8(+)CTLs, may be a critical parameter for achieving clinical activity against solid tumors.
ISSN:2326-6074
DOI:10.1158/2326-6066.CIR-14-0200