دورية أكاديمية
EBAG9 silencing exerts an immune checkpoint function without aggravating adverse effects.
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.) |
References: | Oncogenesis. 2014 Nov 03;3:e126. (PMID: 25365482) N Engl J Med. 2014 Oct 16;371(16):1507-17. (PMID: 25317870) Science. 2013 Mar 29;339(6127):1546-58. (PMID: 23539594) Cell. 2019 Aug 22;178(5):1189-1204.e23. (PMID: 31442407) Mol Ther. 2010 Apr;18(4):843-51. (PMID: 20179677) Cell. 2017 Feb 9;168(4):724-740. (PMID: 28187291) J Clin Oncol. 2018 Aug 1;36(22):2267-2280. (PMID: 29812997) N Engl J Med. 2019 May 2;380(18):1726-1737. (PMID: 31042825) Nat Immunol. 2013 Oct;14(10):1064-72. (PMID: 23955661) Am J Hematol. 2017 Jan;92(1):E11-E13. (PMID: 27779774) J Clin Invest. 2005 Jun;115(6):1616-26. (PMID: 15931392) Immunity. 2011 Aug 26;35(2):161-8. (PMID: 21867926) Nature. 2019 Jul;571(7764):270-274. (PMID: 31207604) Nature. 2019 Mar;567(7749):530-534. (PMID: 30814732) Mol Oncol. 2015 Aug;9(7):1348-58. (PMID: 25953704) Leuk Lymphoma. 2018 Aug;59(8):1772-1784. (PMID: 29019452) Cancer Immunol Immunother. 2019 Jul;68(7):1195-1209. (PMID: 31177329) PLoS One. 2012;7(8):e44219. (PMID: 22937164) JCI Insight. 2022 Jun 8;7(11):. (PMID: 35482418) Cancer Discov. 2018 Oct;8(10):1219-1226. (PMID: 30135176) Immunol Res. 2005;31(1):13-24. (PMID: 15591619) Immunol Rev. 2014 Jan;257(1):127-44. (PMID: 24329794) OMICS. 2012 May;16(5):284-7. (PMID: 22455463) Blood. 2017 Mar 2;129(9):1113-1123. (PMID: 28115373) Mol Ther. 2017 Sep 6;25(9):2189-2201. (PMID: 28676342) Bioinformatics. 2004 Dec 12;20(18):3710-5. (PMID: 15297299) Nat Methods. 2016 Jul;13(7):577-80. (PMID: 27240256) PLoS Comput Biol. 2020 Feb 25;16(2):e1007664. (PMID: 32097405) Hum Gene Ther Clin Dev. 2014 Dec;25(4):218-28. (PMID: 25381930) Bioinformatics. 2019 Jun 1;35(12):2084-2092. (PMID: 30395178) Sci Transl Med. 2013 Mar 20;5(177):177ra38. (PMID: 23515080) Mol Ther. 2014 Nov;22(11):1983-91. (PMID: 25048215) Immunity. 2016 Feb 16;44(2):380-90. (PMID: 26885860) Nat Rev Immunol. 2015 Jan;15(1):45-56. (PMID: 25534622) Gene Ther. 2000 Jun;7(12):1063-6. (PMID: 10871756) Cell Syst. 2015 Dec 23;1(6):417-425. (PMID: 26771021) J Biol Chem. 2003 Jun 20;278(25):22998-3007. (PMID: 12672804) Cancer Discov. 2016 Jun;6(6):664-79. (PMID: 27076371) J Clin Invest. 2019 Mar 21;129(6):2210-2221. (PMID: 30896447) Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50. (PMID: 16199517) Nat Rev Cancer. 2012 Mar 01;12(4):307-13. (PMID: 22378190) Mol Ther. 2018 Jan 3;26(1):269-279. (PMID: 29203150) N Engl J Med. 2017 Dec 28;377(26):2545-2554. (PMID: 29226764) Immunol Cell Biol. 2011 Mar;89(3):396-407. (PMID: 21301477) Nat Rev Immunol. 2015 Aug;15(8):486-99. (PMID: 26205583) Mol Ther. 2018 Aug 1;26(8):1906-1920. (PMID: 30078440) Annu Rev Immunol. 2007;25:267-96. (PMID: 17134371) Cancer Immunol Res. 2015 Apr;3(4):368-79. (PMID: 25576337) Nat Immunol. 2022 May;23(5):757-767. (PMID: 35437325) Blood. 2018 May 24;131(21):2320-2330. (PMID: 29666117) Nat Methods. 2017 Apr;14(4):417-419. (PMID: 28263959) J Clin Invest. 2008 Apr;118(4):1398-404. (PMID: 18317595) Nat Rev Clin Oncol. 2020 Mar;17(3):147-167. (PMID: 31848460) J Clin Invest. 2009 Aug;119(8):2136-40. (PMID: 19620775) Nat Immunol. 2013 Oct;14(10):1014-22. (PMID: 24048123) Blood. 2016 Jun 30;127(26):3321-30. (PMID: 27207799) Clin Cancer Res. 2016 Apr 15;22(8):1875-84. (PMID: 27084741) Nat Immunol. 2020 Aug;21(8):848-856. (PMID: 32632291) J Clin Invest. 2009 Aug;119(8):2184-203. (PMID: 19620783) Science. 2020 Feb 28;367(6481):. (PMID: 32029687) |
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 |
تدمد: | 1525-0024 |
---|---|
DOI: | 10.1016/j.ymthe.2022.07.009 |