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Publications

Journal Article Epublish

PubMed: 39924591 DOI: 10.1038/s41698-025-00828-6

RevCAR-mediated T-cell response against PD-L1-expressing cells turns suppression into activation.

NPJ Precis Oncol 9(1):42

Authors: Eugenia Crespo, Liliana R Loureiro, Antonia Stammberger, Lydia Hoffmann, Nicole Berndt, Anja Hoffmann, Claudia Dagostino, Karla E G Soto, Luise Rupp, Claudia Arndt, Martin Schneider, Claudia R Ball, Michael Bachmann, Marc Schmitz, Anja Feldmann

Affiliations

  • Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
  • Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany.
  • Department for Translational Medical Oncology, National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany. Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany.
  • Mildred Scheel Early Career Center, Faculty of Medicine Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany.
  • Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.
  • Department for Translational Medical Oncology, National Center for Tumor Diseases Dresden (NCT/UCC), a partnership between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, and Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
  • Translational Medical Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany.
  • Faculty of Biology, TUD Dresden University of Technology, Dresden, Germany.
  • German Cancer Consortium (DKTK), partner site Dresden, Dresden, Germany.
  • Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
  • German Cancer Consortium (DKTK), partner site Dresden, Dresden, Germany.
  • National Center for Tumor Diseases (NCT), partner site Dresden, Dresden, Germany.
  • National Center for Tumor Diseases (NCT), partner site Dresden, Dresden, Germany.
  • Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany.
  • German Cancer Consortium (DKTK), partner site Dresden, Dresden, Germany.
  • National Center for Tumor Diseases (NCT), partner site Dresden, Dresden, Germany.

Abstract

Applying CAR T-cell therapy to treat solid tumors is especially challenging due to the immunosuppressive tumor microenvironment (TME). While our modular RevCAR system enhances the safety and controllability of CAR T-cell therapy, effectively targeting solid tumors remains difficult. Since PD-L1 is an immune checkpoint frequently upregulated by cancer cells and their microenvironment, it is a relevant target for solid tumors. Here, we introduce a novel PD-L1 RevTM capable of redirecting RevCAR T-cells to specifically target and kill PD-L1-expressing tumor cells, becoming activated and secreting pro-inflammatory cytokines. This is shown in vitro with monolayer and 3D models, including patient-derived cultures, and in vivo. Furthermore, we demonstrate in vitro and in vivo an AND-gated targeting of cells simultaneously expressing PD-L1 and another tumor-associated antigen by the Dual RevCAR system. Our findings suggest that RevCAR-mediated targeting of PD-L1 could be a promising therapeutic approach for modulating the TME and improving solid tumor treatment.

MeSH

Cells, Neoplasms, Therapeutics, T-Lymphocytes