دورية أكاديمية
أعرض في EDS

EBAG9 silencing exerts an immune checkpoint function without aggravating adverse effects.

التفاصيل البيبلوغرافية
العنوان: EBAG9 silencing exerts an immune checkpoint function without aggravating adverse effects.
المؤلفون: Wirges A; Translational Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany., Bunse M; Microenvironmental Regulation in Autoimmunity and Cancer, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany., Joedicke JJ; Translational Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany., Blanc E; Core Unit Bioinformatics, Berlin Institute of Health, 10117 Berlin, Germany., Gudipati V; Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, 1090 Vienna, Austria., Moles MW; Translational Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany., Shiku H; Department of Personalized Cancer Immunotherapy, Mie University Graduate School of Medicine, Tsu city, Mie, 514-8507, Japan., Beule D; Core Unit Bioinformatics, Berlin Institute of Health, 10117 Berlin, Germany., Huppa JB; Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied Immunology, 1090 Vienna, Austria., Höpken UE; Microenvironmental Regulation in Autoimmunity and Cancer, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany., Rehm A; Translational Tumorimmunology, Max-Delbrück-Center for Molecular Medicine, 13125 Berlin, Germany. Electronic address: arehm@mdc-berlin.de.
المصدر: Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2022 Nov 02; Vol. 30 (11), pp. 3358-3378. Date of Electronic Publication: 2022 Jul 12.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Cell Press Country of Publication: United States NLM ID: 100890581 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1525-0024 (Electronic) Linking ISSN: 15250016 NLM ISO Abbreviation: Mol Ther Subsets: MEDLINE
أسماء مطبوعة: Publication: 2017- : Cambridge, MA : Cell Press
Original Publication: San Diego, CA : Academic Press, 2000-
مواضيع طبية MeSH: Immunotherapy, Adoptive* , Neoplasms*/therapy , Antigens, Neoplasm*/genetics, Animals ; Female ; Humans ; Mice ; MicroRNAs/genetics ; Receptors, Antigen, T-Cell/genetics ; T-Lymphocytes, Cytotoxic ; Gene Silencing ; Immune Checkpoint Proteins
مستخلص: Chimeric antigen receptor (CAR) T cells have revolutionized treatment of B cell malignancies. However, enhancing the efficacy of engineered T cells without compromising their safety is warranted. The estrogen receptor-binding fragment-associated antigen 9 (EBAG9) inhibits release of cytolytic enzymes from cytotoxic T lymphocytes. Here, we examined the potency of EBAG9 silencing for the improvement of adoptive T cell therapy. MicroRNA (miRNA)-mediated EBAG9 downregulation in transplanted cytolytic CD8+ T cells (CTLs) from immunized mice improved their cytolytic competence in a tumor model. In tolerant female recipient mice that received organ transplants, a minor histocompatibility antigen was turned into a rejection antigen by Ebag9 deletion, indicating an immune checkpoint function for EBAG9. Considerably fewer EBAG9-silenced human CAR T cells were needed for tumor growth control in a xenotransplantation model. Transcriptome profiling did not reveal additional risks regarding genotoxicity or aberrant differentiation. A single-step retrovirus transduction process links CAR or TCR expression with miRNA-mediated EBAG9 downregulation. Despite higher cytolytic efficacy, release of cytokines associated with cytokine release syndrome remains unaffected. Collectively, EBAG9 silencing enhances effector capacity of TCR- and CAR-engineered T cells, results in improved tumor eradication, facilitates efficient manufacturing, and decreases the therapeutic dose.
Competing Interests: Declaration of interests A.W., M.B., U.E.H., and A.R. have filed patent applications on the BCMA CAR and on the therapeutic application of EBAG9 modulation, respectively. The authors have declared that no competing conflict of interests exist regarding data acquisition and interpretation. A.R. and U.E.H. received research funding from Fate Therapeutics (San Diego, CA) for work unrelated to the main topic in this manuscript.
(Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)
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فهرسة مساهمة: Keywords: adoptive T cell therapy; cancer immunotherapy; chimeric antigen receptor T cells; cytolytic capacity; hematologic malignancies; leukemia; multiple myeloma; secretory pathway
المشرفين على المادة: 0 (MicroRNAs)
0 (Receptors, Antigen, T-Cell)
0 (EBAG9 protein, mouse)
0 (EBAG9 protein, human)
0 (Immune Checkpoint Proteins)
0 (Antigens, Neoplasm)
تواريخ الأحداث: Date Created: 20220713 Date Completed: 20221108 Latest Revision: 20231103
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC9637585
DOI: 10.1016/j.ymthe.2022.07.009
PMID: 35821635
قاعدة البيانات: MEDLINE
الوصف
تدمد:1525-0024
DOI:10.1016/j.ymthe.2022.07.009