دورية أكاديمية
أعرض في EDS

Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint.

التفاصيل البيبلوغرافية
العنوان: Targeting human Acyl-CoA:cholesterol acyltransferase as a dual viral and T cell metabolic checkpoint.
المؤلفون: Schmidt NM; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK., Wing PAC; Nuffield Department of Medicine, Oxford University, Oxford, UK., Diniz MO; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK., Pallett LJ; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK., Swadling L; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK., Harris JM; Nuffield Department of Medicine, Oxford University, Oxford, UK., Burton AR; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK., Jeffery-Smith A; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK., Zakeri N; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK., Amin OE; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK., Kucykowicz S; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK., Heemskerk MH; Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands., Davidson B; Division of Surgery, University College London, London, UK.; Royal Free London NHS Foundation Trust, London, UK., Meyer T; Royal Free London NHS Foundation Trust, London, UK.; Cancer Institute, University College London, London, UK., Grove J; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK., Stauss HJ; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK., Pineda-Torra I; Division of Medicine, University College London, London, UK., Jolly C; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK., Jury EC; Division of Medicine, University College London, London, UK., McKeating JA; Nuffield Department of Medicine, Oxford University, Oxford, UK., Maini MK; Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK. m.maini@ucl.ac.uk.
المصدر: Nature communications [Nat Commun] 2021 May 14; Vol. 12 (1), pp. 2814. Date of Electronic Publication: 2021 May 14.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Enzyme Inhibitors/*pharmacology , Hepatitis B virus/*drug effects , Sterol O-Acyltransferase/*antagonists & inhibitors , T-Lymphocytes/*drug effects , T-Lymphocytes/*metabolism, CD8-Positive T-Lymphocytes/drug effects ; CD8-Positive T-Lymphocytes/immunology ; CD8-Positive T-Lymphocytes/metabolism ; Carcinoma, Hepatocellular/drug therapy ; Carcinoma, Hepatocellular/virology ; Drug Therapy, Combination ; Enzyme Inhibitors/administration & dosage ; Hepatitis B virus/immunology ; Hepatitis B virus/pathogenicity ; Hepatitis B, Chronic/drug therapy ; Humans ; Immune Checkpoint Inhibitors/administration & dosage ; Immune Checkpoint Inhibitors/pharmacology ; In Vitro Techniques ; Liver/drug effects ; Liver/immunology ; Liver/virology ; Liver Neoplasms/drug therapy ; Liver Neoplasms/virology ; T-Lymphocytes/immunology
مستخلص: Determining divergent metabolic requirements of T cells, and the viruses and tumours they fail to combat, could provide new therapeutic checkpoints. Inhibition of acyl-CoA:cholesterol acyltransferase (ACAT) has direct anti-carcinogenic activity. Here, we show that ACAT inhibition has antiviral activity against hepatitis B (HBV), as well as boosting protective anti-HBV and anti-hepatocellular carcinoma (HCC) T cells. ACAT inhibition reduces CD8 +  T cell neutral lipid droplets and promotes lipid microdomains, enhancing TCR signalling and TCR-independent bioenergetics. Dysfunctional HBV- and HCC-specific T cells are rescued by ACAT inhibitors directly ex vivo from human liver and tumour tissue respectively, including tissue-resident responses. ACAT inhibition enhances in vitro responsiveness of HBV-specific CD8 + T cells to PD-1 blockade and increases the functional avidity of TCR-gene-modified T cells. Finally, ACAT regulates HBV particle genesis in vitro, with inhibitors reducing both virions and subviral particles. Thus, ACAT inhibition provides a paradigm of a metabolic checkpoint able to constrain tumours and viruses but rescue exhausted T cells, rendering it an attractive therapeutic target for the functional cure of HBV and HBV-related HCC.
References: J Exp Med. 2001 Dec 3;194(11):1675-81. (PMID: 11733581)
Nat Commun. 2019 May 9;10(1):2123. (PMID: 31073180)
Gastroenterology. 2014 Apr;146(4):1070-83. (PMID: 24361467)
Cell Metab. 2016 Jun 14;23(6):963-964. (PMID: 27304495)
Front Immunol. 2017 Nov 03;8:1467. (PMID: 29163534)
JAMA Oncol. 2021 Jan 01;7(1):113-123. (PMID: 33090190)
Cell. 2008 Jul 11;134(1):97-111. (PMID: 18614014)
Haematologica. 2011 Mar;96(3):477-81. (PMID: 21109688)
Nat Immunol. 2018 Dec;19(12):1330-1340. (PMID: 30420624)
Sci Rep. 2017 Mar 06;7:43446. (PMID: 28262670)
Nat Rev Mol Cell Biol. 2008 Feb;9(2):125-38. (PMID: 18216769)
Hepatology. 2014 Apr;59(4):1415-26. (PMID: 24002931)
Gastroenterology. 2019 Jan;156(2):311-324. (PMID: 30243618)
J Mol Cell Biol. 2013 Dec;5(6):404-15. (PMID: 24163426)
PLoS Pathog. 2019 Aug 8;15(8):e1007874. (PMID: 31393946)
Cell Death Dis. 2020 Feb 6;11(2):105. (PMID: 32029741)
Front Immunol. 2017 Nov 27;8:1664. (PMID: 29230226)
Nat Med. 2010 Aug;16(8):880-6. (PMID: 20622859)
Nature. 2019 Mar;567(7747):257-261. (PMID: 30814741)
J Hepatol. 2019 Nov;71(5):900-907. (PMID: 31306680)
Front Immunol. 2017 Nov 24;8:1636. (PMID: 29225604)
J Lipid Res. 1999 Jul;40(7):1317-27. (PMID: 10393217)
Eur J Immunol. 2012 Dec;42(12):3174-9. (PMID: 22949370)
J Biol Chem. 2012 Dec 14;287(51):42664-74. (PMID: 23091059)
Nat Immunol. 2013 May;14(5):489-99. (PMID: 23563690)
Cell Metab. 2019 Jul 2;30(1):143-156.e5. (PMID: 31031094)
J Cell Biol. 1999 Oct 18;147(2):447-61. (PMID: 10525547)
Trends Microbiol. 2011 Jul;19(7):368-75. (PMID: 21530270)
Science. 2017 Mar 31;355(6332):1428-1433. (PMID: 28280247)
J Virol. 2001 Jun;75(11):5108-18. (PMID: 11333892)
Nat Rev Immunol. 2019 May;19(5):324-335. (PMID: 30820043)
J Hepatol. 2015 Apr;62(4):956-67. (PMID: 25595883)
Trends Immunol. 2019 Aug;40(8):735-747. (PMID: 31255505)
J Hepatol. 2006 Aug;45(2):178-81. (PMID: 16797771)
J Biol Chem. 1982 Jul 10;257(13):7770-7. (PMID: 7085648)
Cell Metab. 2017 Jul 5;26(1):49-70. (PMID: 28683294)
J Infect Dis. 2018 Mar 13;217(7):1044-1054. (PMID: 29300924)
Life Sci Alliance. 2019 Mar 27;2(2):. (PMID: 30918010)
Antiviral Res. 2017 Dec;148:5-14. (PMID: 29074218)
Sci Transl Med. 2020 Nov 25;12(571):. (PMID: 33239389)
J Hepatol. 2014 Dec;61(6):1212-9. (PMID: 25016223)
Science. 2017 Mar 31;355(6332):1423-1427. (PMID: 28280249)
Liver Int. 2017 Nov;37(11):1632-1641. (PMID: 28328162)
Cell Res. 2010 Oct;20(10):1089-91. (PMID: 20805845)
J Natl Cancer Inst. 2013 Aug 21;105(16):1172-87. (PMID: 23852952)
Cardiovasc Drug Rev. 2003 Spring;21(1):33-50. (PMID: 12595916)
Nat Rev Gastroenterol Hepatol. 2019 Nov;16(11):662-675. (PMID: 31548710)
Nature. 2016 Mar 31;531(7596):651-5. (PMID: 26982734)
Annu Rev Cancer Biol. 2019 Mar;3:55-75. (PMID: 37539076)
J Hepatol. 2011 Jul;55(1):103-10. (PMID: 21145860)
J Gen Virol. 2014 Sep;95(Pt 9):1900-1910. (PMID: 24859394)
Immunity. 2016 May 17;44(5):1091-101. (PMID: 27192576)
J Exp Med. 2017 Jun 5;214(6):1567-1580. (PMID: 28526759)
Cell. 2017 Jun 15;169(7):1342-1356.e16. (PMID: 28622514)
CA Cancer J Clin. 2018 Nov;68(6):394-424. (PMID: 30207593)
Nat Rev Mol Cell Biol. 2017 Jun;18(6):361-374. (PMID: 28356571)
J Physiol. 1928 Nov 9;66(3):249-61. (PMID: 16993988)
Oncotarget. 2019 Aug 27;10(50):5194-5206. (PMID: 31497249)
Lancet Gastroenterol Hepatol. 2018 Mar;3(3):192-202. (PMID: 29870733)
Nat Commun. 2019 Oct 1;10(1):4451. (PMID: 31575864)
Nat Cell Biol. 2006 Nov;8(11):1270-6. (PMID: 17060905)
J Clin Invest. 2014 Feb;124(2):712-24. (PMID: 24463447)
Cell Microbiol. 2020 Dec;22(12):e13250. (PMID: 32799415)
J Virol. 2007 Mar;81(6):2940-9. (PMID: 17202217)
Gastroenterology. 2019 May;156(6):1862-1876.e9. (PMID: 30711630)
J Biol Chem. 2000 Sep 8;275(36):28083-92. (PMID: 10846185)
J Hepatol. 2016 Apr;64(1 Suppl):S32-S40. (PMID: 27084034)
معلومات مُعتمدة: 26813 United Kingdom CRUK_ Cancer Research UK; MR/R022011/1 United Kingdom MRC_ Medical Research Council; 26603 United Kingdom CRUK_ Cancer Research UK; G0801976 United Kingdom MRC_ Medical Research Council; 101849/Z/13/A United Kingdom WT_ Wellcome Trust; G0400802 United Kingdom MRC_ Medical Research Council; MRF_MRF-044-0001-RG-SWADL United Kingdom MRF MRF; 200838/Z/16/Z United Kingdom WT_ Wellcome Trust; G1100247 United Kingdom MRC_ Medical Research Council; 214191/Z/18/Z United Kingdom WT_ Wellcome Trust; United Kingdom WT_ Wellcome Trust
المشرفين على المادة: 0 (Enzyme Inhibitors)
0 (Immune Checkpoint Inhibitors)
EC 2.3.1.26 (Sterol O-Acyltransferase)
تواريخ الأحداث: Date Created: 20210515 Date Completed: 20210603 Latest Revision: 20240402
رمز التحديث: 20240402
مُعرف محوري في PubMed: PMC8121939
DOI: 10.1038/s41467-021-22967-7
PMID: 33990561
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-021-22967-7