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Immune-restoring CAR-T cells display antitumor activity and reverse immunosuppressive TME in a humanized ccRCC mouse model.
Wang, Yufei; Cho, Jae-Won; Kastrunes, Gabriella; Buck, Alicia; Razimbaud, Cecile; Culhane, Aedin C; Sun, Jiusong; Braun, David A; Choueiri, Toni K; Wu, Catherine J; Jones, Kristen; Nguyen, Quang-De; Zhu, Zhu; Wei, Kevin; Zhu, Quan; Signoretti, Sabina; Freeman, Gordon J; Hemberg, Martin; Marasco, Wayne A.
  • Wang Y; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Cho JW; Harvard Medical School, Boston, MA 02215, USA.
  • Kastrunes G; Harvard Medical School, Boston, MA 02215, USA.
  • Buck A; Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • Razimbaud C; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Culhane AC; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Sun J; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Braun DA; School of Medicine, University of Limerick, V94 T9PX Limerick, Ireland.
  • Choueiri TK; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Wu CJ; Harvard Medical School, Boston, MA 02215, USA.
  • Jones K; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Nguyen QD; Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT 06525, USA.
  • Zhu Z; Harvard Medical School, Boston, MA 02215, USA.
  • Wei K; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Zhu Q; Harvard Medical School, Boston, MA 02215, USA.
  • Signoretti S; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Freeman GJ; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Hemberg M; Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Marasco WA; Harvard Medical School, Boston, MA 02215, USA.
iScience ; 27(2): 108879, 2024 Feb 16.
Article en En | MEDLINE | ID: mdl-38327771
ABSTRACT
One of the major barriers that have restricted successful use of chimeric antigen receptor (CAR) T cells in the treatment of solid tumors is an unfavorable tumor microenvironment (TME). We engineered CAR-T cells targeting carbonic anhydrase IX (CAIX) to secrete anti-PD-L1 monoclonal antibody (mAb), termed immune-restoring (IR) CAR G36-PDL1. We tested CAR-T cells in a humanized clear cell renal cell carcinoma (ccRCC) orthotopic mouse model with reconstituted human leukocyte antigen (HLA) partially matched human leukocytes derived from fetal CD34+ hematopoietic stem cells (HSCs) and bearing human ccRCC skrc-59 cells under the kidney capsule. G36-PDL1 CAR-T cells, haploidentical to the tumor cells, had a potent antitumor effect compared to those without immune-restoring effect. Analysis of the TME revealed that G36-PDL1 CAR-T cells restored active antitumor immunity by promoting tumor-killing cytotoxicity, reducing immunosuppressive cell components such as M2 macrophages and exhausted CD8+ T cells, and enhancing T follicular helper (Tfh)-B cell crosstalk.
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Texto completo: 1 Banco de datos: MEDLINE Idioma: En Año: 2024 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Search on Google

Texto completo: 1 Banco de datos: MEDLINE Idioma: En Año: 2024 Tipo del documento: Article