{
  "abstract": "Background Boosting the performance of chimeric antigen receptor T (CAR-T) cell therapy in solid tumors may provide a substantial advantage for patients with cancer. Recognizing the vital role of the nuclear factor of activated T cells (NFAT) in T cell function, we hypothesized the strategic regulation of NFAT activity by targeting c-Jun N-terminal kinases (JNK) can bolster the tumor-eradicating potential of CAR-T cells.Methods We developed a lentivirally encoded short-hairpin RNA for stable knockdown of JNK in CAR-T cells. CAR-T cells targeting human epidermal growth factor receptor 2 were produced from human peripheral blood. Functionality was tested in vitro and in two xenograft models of human ovarian cancer.Results JNK knockdown in CAR-T cells suppressed antigen-induced stimulation and helper T cell cytokine production, while enhancing antitumor cytotoxicity in vitro and in ovarian cancer xenograft experiments. Mechanistically, JNK knockdown altered NFAT signaling to facilitate NFATc1-dependent transcription, leading to elevated levels of granzyme B expression.Conclusions JNK signaling is a significant regulator of CAR-T cell cytotoxicity, offering a potential strategy to directly enhance CAR-T effectiveness in human cancer therapies.",
  "authors": [
    {
      "affiliations": [
        "Department of Microbiology, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA"
      ],
      "name": "Charles Joseph Kuhlmann"
    },
    {
      "affiliations": [
        "Department of Microbiology, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA"
      ],
      "name": "Chloe E Jepson"
    },
    {
      "affiliations": [
        "Department of Microbiology, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA"
      ],
      "name": "Madison T Blucas"
    },
    {
      "affiliations": [
        "Department of Microbiology, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA"
      ],
      "name": "Fatema M Suleiman"
    },
    {
      "affiliations": [
        "Department of Microbiology, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA"
      ],
      "name": "Anusha Manda"
    },
    {
      "affiliations": [
        "Department of Pathology, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA"
      ],
      "name": "Yoshiko N Kamata"
    },
    {
      "affiliations": [
        "Department of Microbiology, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA",
        "O’Neal Comprehensive Cancer Center at UAB, Birmingham, Alabama, USA"
      ],
      "name": "Masakazu Kamata"
    }
  ],
  "title": "JNK knockdown enhances CAR-T cell cytotoxicity through elevated NFATc1-dependent transcription in preclinical ovarian cancer models",
  "uid": "4ba1b6ab-61ea-5730-9b0c-1b0529d9846d"
}