Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors.

Autor: Cadilha BL; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany. bcadilha@gmail.com sebastian.kobold@med.uni-muenchen.de., Benmebarek MR; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Dorman K; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany.; Department of Internal Medicine III, University of Munich, Munich, Germany., Oner A; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Lorenzini T; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Obeck H; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Vänttinen M; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Di Pilato M; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Department of Immunology, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA., Pruessmann JN; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Department of Dermatology, Allergology, and Venerology, University of Lübeck, Lübeck, Germany., Stoiber S; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Huynh D; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Märkl F; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Seifert M; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Manske K; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Suarez-Gosalvez J; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Zeng Y; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Lesch S; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Karches CH; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Heise C; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Gottschlich A; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Thomas M; Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.; Technical University of Munich, School of Life Sciences Weihenstephan, Freising, Germany., Marr C; Institute of Computational Biology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany., Zhang J; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Pandey D; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Feuchtinger T; Department of Pediatric Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Dr. von Hauner University Children's Hospital, Ludwig Maximilian University Munich.; German Center for Infection Research (DZIF), Munich, Germany., Subklewe M; Department of Internal Medicine III, University of Munich, Munich, Germany., Mempel TR; Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Endres S; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany., Kobold S; Center of Integrated Protein Science Munich and Division of Clinical Pharmacology, Department of Medicine IV, Klinikum der Universität München, Munich, Germany. bcadilha@gmail.com sebastian.kobold@med.uni-muenchen.de.; German Center for Translational Cancer Research (DKTK), Partner Site Munich, Germany.; Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), Neuherberg, Germany.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2021 Jun 09; Vol. 7 (24). Date of Electronic Publication: 2021 Jun 09 (Print Publication: 2021).
DOI: 10.1126/sciadv.abi5781
Abstrakt: CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (T reg ) cells suppress the immune response via inhibitory factors such as transforming growth factor-β (TGF-β). T reg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8 + T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-β shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.
(Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)
Databáze: MEDLINE
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