TY  - JOUR
T1  - Silencing JNK Potentiates CAR-T Cell–Mediated Tumor Killing by Augmenting NFATc1-Driven Transcriptional Programs in Preclinical Ovarian Cancer Models
A1  - Helena Sofia Martins
A1  - Ana Rita Teixeira
A1  - Daniel Mark Johnson
A1  - Ethan Robert Williams
JF  - Archive of International Journal of Cancer and Allied Science
JO  - Arch Int J Cancer Allied Sci
SN  - 3108-4834
Y1  - 2021
VL  - 1
IS  - 1
DO  - 10.51847/8gPM3QLi9R
SP  - 119
EP  - 136
N2  - Improving the activity of chimeric antigen receptor T (CAR-T) cell therapy in solid cancers represents a critical unmet need in oncology. Because nuclear factor of activated T cells (NFAT) signaling governs multiple aspects of T cell behavior, we proposed that selective control of NFAT activity via inhibition of c-Jun N-terminal kinases (JNK) could reprogram CAR-T cells toward superior tumor-eliminating capacity. A lentiviral system encoding short-hairpin RNA was established to achieve durable JNK suppression in CAR-T cells. Human epidermal growth factor receptor 2–specific CAR-T cells were generated from peripheral blood T cells and evaluated using functional assays in vitro as well as two independent human ovarian cancer xenograft models.

CAR-T cells with reduced JNK expression exhibited diminished antigen-driven activation and lower helper T cell cytokine output but demonstrated markedly enhanced cytotoxic activity against tumor cells both in culture and in vivo. Mechanistic analyses showed that JNK silencing reoriented NFAT signaling toward preferential NFATc1-dependent transcription, resulting in increased granzyme B production. JNK functions as a central signaling checkpoint that restrains CAR-T cell cytotoxicity, and its inhibition offers a rational strategy to directly amplify CAR-T antitumor efficacy in human cancer treatment.
UR  - https://smerpub.com/article/silencing-jnk-potentiates-car-t-cellmediated-tumor-killing-by-augmenting-nfatc1-driven-transcriptio-lqxvgrj2wxoyxp1
ER  -