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

CD8-Positive T-Lymphocytes / drug effects Carcinoma, Hepatocellular / drug therapy Drug Therapy, Combination Enzyme Inhibitors / administration & dosage Hepatitis B virus / drug effects Hepatitis B, Chronic / drug therapy Humans Immune Checkpoint Inhibitors / administration & dosage In Vitro Techniques Liver / drug effects Liver Neoplasms / drug therapy Sterol O-Acyltransferase / antagonists & inhibitors T-Lymphocytes / drug effects

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
14 05 2021
Historique:
received: 10 08 2020
accepted: 09 04 2021
entrez: 15 5 2021
pubmed: 16 5 2021
medline: 4 6 2021
Statut: epublish

Résumé

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

Identifiants

DOI: 10.1038/s41467-021-22967-7 PMID: 33990561 PMC: PMC8121939
pubmed: 33990561
doi: 10.1038/s41467-021-22967-7
pii: 10.1038/s41467-021-22967-7
pmc: PMC8121939
doi:

Substances chimiques

Enzyme Inhibitors 0
Immune Checkpoint Inhibitors 0
Sterol O-Acyltransferase EC 2.3.1.26

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

2814

Subventions

Organisme : Cancer Research UK
ID : 26813
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R022011/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 26603
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0801976
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 101849/Z/13/A
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0400802
Pays : United Kingdom
Organisme : MRF
ID : MRF_MRF-044-0001-RG-SWADL
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 200838/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1100247
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 214191/Z/18/Z
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom

Références

Geneva: World Health Organization. Global Hepatitis Report 2017 (2017).
Xia, Y. & Liang, T. J. Development of direct-acting antiviral and host-targeting agents for treatment of hepatitis B virus infection. Gastroenterology 156, 311–324 (2019).
pubmed: 30243618 doi: 10.1053/j.gastro.2018.07.057
Maini, M. K. & Pallett, L. J. Defective T cell immunity in hepatitis B virus infection: why therapeutic vaccination needs a helping hand. Lancet Gastroenterol. Hepatol. 3, 192–202 (2018).
pubmed: 29870733 doi: 10.1016/S2468-1253(18)30007-4
Maini, M. K. & Burton, A. R. Restoring, releasing or replacing adaptive immunity in chronic hepatitis B. Nat. Rev. Gastroenterol. Hepatol. 16, 662–675 (2019).
pubmed: 31548710 doi: 10.1038/s41575-019-0196-9
Papatheodoridis, G. V., Chan, H. L.-Y., Hansen, B. E., Janssen, H. L. A. & Lampertico, P. Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. J. Hepatol. 62, 956–967 (2015).
pubmed: 25595883 doi: 10.1016/j.jhep.2015.01.002
Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).
pubmed: 30207593 doi: 10.3322/caac.21492
Parmiani, G. & Anichini, A. T cell infiltration and prognosis in HCC patients. J. Hepatol. 45, 178–181 (2006).
pubmed: 16797771 doi: 10.1016/j.jhep.2006.06.005
Flecken, T. et al. Immunodominance and functional alterations of tumor‐associated antigen‐specific CD8+ T‐cell responses in hepatocellular carcinoma. Hepatology 59, 1415–1426 (2014).
pubmed: 24002931 doi: 10.1002/hep.26731
Dougan, M., Dranoff, G. & Dougan, S. K. Cancer immunotherapy: beyond checkpoint blockade. Annu. Rev. Cancer Biol. 3, 55–75 (2019).
doi: 10.1146/annurev-cancerbio-030518-055552
Pinter, M., Jain, R. K. & Duda, D. G. The current landscape of immune checkpoint blockade in hepatocellular carcinoma: a review. JAMA Oncol. 7, 113–123 (2021).
pubmed: 33090190 doi: 10.1001/jamaoncol.2020.3381 pmcid: 8265820
Gane, E. et al. Anti-PD-1 blockade with nivolumab with and without therapeutic vaccination for virally suppressed chronic hepatitis B: a pilot study. J. Hepatol. 71, 900–907 (2019).
pubmed: 31306680 doi: 10.1016/j.jhep.2019.06.028
O’Sullivan, D., Sanin, D. E., Pearce, E. J. & Pearce, E. L. Metabolic interventions in the immune response to cancer. Nat. Rev. Immunol. 19, 324–335 (2019).
pubmed: 30820043 doi: 10.1038/s41577-019-0140-9
Andrejeva, G. & Rathmell, J. C. Similarities and distinctions of cancer and immune metabolism in inflammation and tumors. Cell Metab. 26, 49–70 (2017).
pubmed: 28683294 pmcid: 5555084 doi: 10.1016/j.cmet.2017.06.004
Kedia-Mehta, N. & Finlay, D. K. Competition for nutrients and its role in controlling immune responses. Nat. Commun. 10, 1–8 (2019).
doi: 10.1038/s41467-019-10015-4
Jiang, Y. et al. Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature 567, 257–261 (2019).
pubmed: 30814741 doi: 10.1038/s41586-019-0987-8
Lu, M. et al. A specific cholesterol metabolic pathway is established in a subset of HCCs for tumor growth. J. Mol. Cell Biol. 5, 404–415 (2013).
pubmed: 24163426 pmcid: 3841111 doi: 10.1093/jmcb/mjt039
Cruz, A. L. S. et al. Lipid droplets: platforms with multiple functions in cancer hallmarks. Cell Death Dis. 11, 1–16 (2020).
doi: 10.1038/s41419-020-2297-3
Yang, W. et al. Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nature 531, 651–655 (2016).
pubmed: 26982734 pmcid: 4851431 doi: 10.1038/nature17412
Bengsch, B., Martin, B. & Thimme, R. Restoration of HBV-specific CD8+ T cell function by PD-1 blockade in inactive carrier patients is linked to T cell differentiation. J. Hepatol. 61, 1212–1219 (2014).
pubmed: 25016223 doi: 10.1016/j.jhep.2014.07.005
Zheng, C. et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 169, 1342–1356.e16 (2017).
pubmed: 28622514 doi: 10.1016/j.cell.2017.05.035
Chamberlain, E. N. The cholesterol content of normal tissues and the effect of intravenous injections of cholesterol thereon. J. Physiol. 66, 249–261 (1928).
pubmed: 16993988 pmcid: 1402774 doi: 10.1113/jphysiol.1928.sp002523
Pallett, L. J. et al. IL-2high tissue-resident T cells in the human liver: Sentinels for hepatotropic infection. J. Exp. Med. 214, 1567–1580 (2017).
pubmed: 28526759 pmcid: 5461007 doi: 10.1084/jem.20162115
Ikonen, E. Cellular cholesterol trafficking and compartmentalization. Nat. Rev. Mol. Cell Biol. 9, 125–138 (2008).
pubmed: 18216769 doi: 10.1038/nrm2336
Bietz, A., Zhu, H., Xue, M. & Xu, C. Cholesterol metabolism in T cells. Front. Immunol. 8, 1664 (2017).
pubmed: 29230226 pmcid: 5711771 doi: 10.3389/fimmu.2017.01664
Michelet, X. et al. Metabolic reprogramming of natural killer cells in obesity limits antitumor responses. Nat. Immunol. 19, 1330–1340 (2018).
pubmed: 30420624 doi: 10.1038/s41590-018-0251-7
Herber, D. L. et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat. Med. 16, 880–886 (2010).
pubmed: 20622859 pmcid: 2917488 doi: 10.1038/nm.2172
Calder, P. C. Lipid-laden dendritic cells fail to function. Cell Res. 20, 1089–1091 (2010).
pubmed: 20805845 doi: 10.1038/cr.2010.124
Zumerle, S., Molon, B. & Viola, A. Membrane rafts in T cell activation: a spotlight on CD28 costimulation. Front. Immunol. 8, 1467 (2017).
Sezgin, E., Levental, I., Mayor, S. & Eggeling, C. The mystery of membrane organization: composition, regulation and roles of lipid rafts. Nat. Rev. Mol. Cell Biol. 18, 361–374 (2017).
pubmed: 28356571 pmcid: 5500228 doi: 10.1038/nrm.2017.16
McDonald, G. et al. Normalizing glycosphingolipids restores function in CD4+ T cells from lupus patients. J. Clin. Invest. 124, 712–724 (2014).
pubmed: 24463447 pmcid: 3904606 doi: 10.1172/JCI69571
Janes, P. W., Ley, S. C. & Magee, A. I. Aggregation of lipid rafts accompanies signaling via the T cell antigen receptor. J. Cell Biol. 147, 447–461 (1999).
pubmed: 10525547 pmcid: 2174214 doi: 10.1083/jcb.147.2.447
Hui, E. et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355, 1428–1433 (2017).
pubmed: 28280247 pmcid: 6286077 doi: 10.1126/science.aaf1292
Tavano, R. et al. CD28 interaction with filamin-A controls lipid raft accumulation at the T cell immunological synapse. Nat. Cell Biol. 8, 1270–1276 (2006).
pubmed: 17060905 doi: 10.1038/ncb1492
Martin, M., Schneider, H., Azouz, A. & Rudd, C. E. Cytotoxic t lymphocyte antigen 4 and CD28 modulate cell surface raft expression in their regulation of T cell function. J. Exp. Med 194, 1675–1682 (2001).
pubmed: 11733581 pmcid: 2193535 doi: 10.1084/jem.194.11.1675
Kamphorst, A. O. et al. Rescue of exhausted CD8 T cells by PD-1–targeted therapies is CD28-dependent. Science 355, 1423–1427 (2017).
pubmed: 28280249 pmcid: 5595217 doi: 10.1126/science.aaf0683
Ma, X. et al. Cholesterol induces CD8+ T cell exhaustion in the tumor microenvironment. Cell Metab. 30, 143–156.e5 (2019).
pubmed: 31031094 pmcid: 7061417 doi: 10.1016/j.cmet.2019.04.002
Park, S. L., Gebhardt, T., Mackay, L. K. & Tissue-Resident Memory, T. Cells in cancer immunosurveillance. Trends Immunol. 40, 735–747 (2019).
pubmed: 31255505 doi: 10.1016/j.it.2019.06.002
Tan, A. T. et al. Use of expression profiles of HBV-DNA integrated into genomes of hepatocellular carcinoma cells to select T cells for immunotherapy. Gastroenterology 156, 1862–1876.e9 (2019).
pubmed: 30711630 doi: 10.1053/j.gastro.2019.01.251
Gehring, A. J. et al. Engineering virus-specific T cells that target HBV infected hepatocytes and hepatocellular carcinoma cell lines. J. Hepatol. 55, 103–110 (2011).
pubmed: 21145860 doi: 10.1016/j.jhep.2010.10.025
van Loenen, M. M. et al. Optimization of the HA-1-specific T cell receptor for gene therapy of hematologic malignancies. Haematologica 96, 477–481 (2011).
pubmed: 21109688 doi: 10.3324/haematol.2010.025916
Thomas, S. et al. Framework engineering to produce dominant T cell receptors with enhanced antigen-specific function. Nat. Commun. 10, 1–15 (2019).
doi: 10.1038/s41467-019-12441-w
Chang, C. C. Y. et al. Immunological quantitation and localization of ACAT-1 and ACAT-2 in human liver and ssmall intestine. J. Biol. Chem. 275, 28083–28092 (2000).
pubmed: 10846185 doi: 10.1074/jbc.M003927200
Gavilanes, F., Gonzalez-Ros, J. M. & Peterson, D. L. Structure of hepatitis B surface antigen. Characterization of the lipid components and their association with the viral proteins. J. Biol. Chem. 257, 7770–7777 (1982).
pubmed: 7085648 doi: 10.1016/S0021-9258(18)34448-X
Li, W. & Urban, S. Entry of hepatitis B and hepatitis D virus into hepatocytes: basic insights and clinical implications. J. Hepatol. 64, S32–S40 (2016).
pubmed: 27084034 pmcid: 7114860 doi: 10.1016/j.jhep.2016.02.011
Chakraborty, A. et al. Synchronised infection identifies early rate-limiting steps in the hepatitis B virus life cycle. Cell. Microbiol. 22, e13250 (2020).
pubmed: 32799415 doi: 10.1111/cmi.13250 pmcid: 7611726
Ni, Y. et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology 146, 1070–1083 (2014).
pubmed: 24361467 doi: 10.1053/j.gastro.2013.12.024
Sprinzl, M. F., Oberwinkler, H., Schaller, H. & Protzer, U. Transfer of hepatitis B virus genome by adenovirus vectors into cultured cells and mice: crossing the species barrier. J. Virol. 75, 5108–5118 (2001).
pubmed: 11333892 pmcid: 114916 doi: 10.1128/JVI.75.11.5108-5118.2001
Zhou, W. et al. Predictive model for inflammation grades of chronic hepatitis B: Large-scale analysis of clinical parameters and gene expressions. Liver Int. 37, 1632–1641 (2017).
pubmed: 28328162 doi: 10.1111/liv.13427
Wang, M. et al. Characterization of gene expression profiles in HBV-related liver fibrosis patients and identification of ITGBL1 as a key regulator of fibrogenesis. Sci. Rep. 7, 43446 (2017).
pubmed: 28262670 pmcid: 5337978 doi: 10.1038/srep43446
Liu, H. et al. Differentially expressed intrahepatic genes contribute to control of hepatitis b virus replication in the inactive carrier phase. J. Infect. Dis. 217, 1044–1054 (2018).
pubmed: 29300924 doi: 10.1093/infdis/jix683
Molnár, E. et al. Cholesterol and sphingomyelin drive ligand-independent T cell antigen receptor nanoclustering. J. Biol. Chem. 287, 42664–42674 (2012).
pubmed: 23091059 pmcid: 3522267 doi: 10.1074/jbc.M112.386045
Swamy, M. et al. A cholesterol-based allostery model of T cell receptor phosphorylation. Immunity 44, 1091–1101 (2016).
pubmed: 27192576 doi: 10.1016/j.immuni.2016.04.011
Hu, L. et al. Avasimibe: a novel hepatitis C virus inhibitor that targets the assembly of infectious viral particles. Antivir. Res. 148, 5–14 (2017).
pubmed: 29074218 doi: 10.1016/j.antiviral.2017.10.016
Read, S. A., Tay, E., Shahidi, M., George, J. & Douglas, M. W. Hepatitis C virus infection mediates cholesteryl ester synthesis to facilitate infectious particle production. J. Gen. Virol. 95, 1900–1910 (2014).
pubmed: 24859394 doi: 10.1099/vir.0.065300-0
Qiao, L. & Luo, G. G. Human apolipoprotein E promotes hepatitis B virus infection and production. PLOS Pathog. 15, e1007874 (2019).
pubmed: 31393946 pmcid: 6687101 doi: 10.1371/journal.ppat.1007874
Heaton, N. S. & Randall, G. Multifaceted roles for lipids in viral infection. Trends Microbiol. 19, 368–375 (2011).
pubmed: 21530270 pmcid: 3130080 doi: 10.1016/j.tim.2011.03.007
Kidani, Y. & Bensinger, S. J. Modulating cholesterol homeostasis to build a better T cell. Cell Metab. 23, 963–964 (2016).
pubmed: 27304495 doi: 10.1016/j.cmet.2016.05.015
Robinson, G. A., Waddington, K. E., Pineda-Torra, I. & Jury, E. C. Transcriptional regulation of T cell lipid metabolism: implications for plasma membrane lipid rafts and T cell function. Front. Immunol. 8, 1636 (2017).
Kidani, Y. et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat. Immunol. 14, 489–499 (2013).
pubmed: 23563690 pmcid: 3652626 doi: 10.1038/ni.2570
Bensinger, S. J. et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134, 97–111 (2008).
pubmed: 18614014 pmcid: 2626438 doi: 10.1016/j.cell.2008.04.052
Llaverías, G., Laguna, J. C. & Alegret, M. Pharmacology of the ACAT inhibitor avasimibe (CI-1011). Cardiovasc. Drug Rev. 21, 33–50 (2003).
pubmed: 12595916 doi: 10.1111/j.1527-3466.2003.tb00104.x
Burnett, J. R. et al. Inhibition of ACAT by avasimibe decreases both VLDL and LDL apolipoprotein B production in miniature pigs. J. Lipid Res. 40, 1317–1327 (1999).
pubmed: 10393217 doi: 10.1016/S0022-2275(20)33494-5
Aleksic, M. et al. Different affinity windows for virus and cancer-specific T cell receptors: implications for therapeutic strategies. Eur. J. Immunol. 42, 3174–3179 (2012).
pubmed: 22949370 pmcid: 3776049 doi: 10.1002/eji.201242606
Leone, P. et al. MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells. J. Natl Cancer Inst. 105, 1172–1187 (2013).
pubmed: 23852952 doi: 10.1093/jnci/djt184
Gehring, A. J. et al. The level of viral antigen presented by hepatocytes influences CD8 T cell function. J. Virol. 81, 2940–2949 (2007).
pubmed: 17202217 pmcid: 1866017 doi: 10.1128/JVI.02415-06
Tauber, C. et al. Inefficient induction of circulating TAA-specific CD8+ T cell responses in hepatocellular carcinoma. Oncotarget 10, 5194–5206 (2019).
pubmed: 31497249 pmcid: 6718268 doi: 10.18632/oncotarget.27146
Hao, M. et al. Combination of metabolic intervention and T cell therapy enhances solid tumor immunotherapy. Sci. Transl. Med. 12, eaaz6667 (2020).
Wing, P. A. et al. A dual role for SAMHD1 in regulating HBV cccDNA and RT-dependent particle genesis. Life Sci. Alliance 2, e201900355 (2019).
pubmed: 30918010 pmcid: 6438393 doi: 10.26508/lsa.201900355

Auteurs

Nathalie M Schmidt (NM)

Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK.
ORCID: 0000-0002-9841-8418

Peter A C Wing (PAC)

Nuffield Department of Medicine, Oxford University, Oxford, UK.
ORCID: 0000-0002-2354-3281

Mariana O Diniz (MO)

Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK.

Laura J Pallett (LJ)

Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK.
ORCID: 0000-0002-4161-9462

Leo Swadling (L)

Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK.
ORCID: 0000-0002-0537-6715

James M Harris (JM)

Nuffield Department of Medicine, Oxford University, Oxford, UK.
ORCID: 0000-0003-1880-3496

Alice R Burton (AR)

Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK.

Anna Jeffery-Smith (A)

Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK.

Nekisa Zakeri (N)

Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK.
ORCID: 0000-0003-1167-1160

Oliver E Amin (OE)

Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK.
ORCID: 0000-0003-3663-1253

Stephanie Kucykowicz (S)

Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK.

Mirjam H Heemskerk (MH)

Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
ORCID: 0000-0001-6320-9133

Brian Davidson (B)

Division of Surgery, University College London, London, UK.
Royal Free London NHS Foundation Trust, London, UK.

Tim Meyer (T)

Royal Free London NHS Foundation Trust, London, UK.
Cancer Institute, University College London, London, UK.

Joe Grove (J)

Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK.
ORCID: 0000-0001-5390-7579

Hans J Stauss (HJ)

Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK.
ORCID: 0000-0003-4340-7911

Ines Pineda-Torra (I)

Division of Medicine, University College London, London, UK.
ORCID: 0000-0002-7349-2208

Clare Jolly (C)

Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK.
ORCID: 0000-0002-4603-2281

Elizabeth C Jury (EC)

Division of Medicine, University College London, London, UK.
ORCID: 0000-0002-2389-3396

Jane A McKeating (JA)

Nuffield Department of Medicine, Oxford University, Oxford, UK.
ORCID: 0000-0002-7229-5886

Mala K Maini (MK)

Division of Infection & Immunity, Institute of Immunity & Transplantation, University College London, London, UK. m.maini@ucl.ac.uk.
ORCID: 0000-0001-6384-1462

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Classifications MeSH

questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › Lymphocytes T CD8+ › Targeting human Acyl-CoA:cholesterol...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Tumeurs du foie › Carcinome hépatocellulaire › Targeting human Acyl-CoA:cholesterol...
questionsmedicales.fr › Thérapeutique › Traitement médicamenteux › Association de médicaments › Targeting human Acyl-CoA:cholesterol...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Mécanismes moléculaires de l'action pharmacologique › Antienzymes › Targeting human Acyl-CoA:cholesterol...
questionsmedicales.fr › Virus › Virus de l'hépatite › Hepadnaviridae › Orthohepadnavirus › Virus de l'hépatite B › Targeting human Acyl-CoA:cholesterol...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Maladie chronique › Hépatite chronique › Hépatite B chronique › Targeting human Acyl-CoA:cholesterol...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Targeting human Acyl-CoA:cholesterol...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Antinéoplasiques immunologiques › Inhibiteurs de points de contrôle immunitaires › Targeting human Acyl-CoA:cholesterol...
questionsmedicales.fr › Techniques d'investigation › Techniques in vitro › Targeting human Acyl-CoA:cholesterol...
questionsmedicales.fr › Système digestif › Foie › Targeting human Acyl-CoA:cholesterol...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Tumeurs du foie › Targeting human Acyl-CoA:cholesterol...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Acyltransferases › Sterol O-acyltransferase › Targeting human Acyl-CoA:cholesterol...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Leucocytes › Agranulocytes › Lymphocytes › Lymphocytes T › Targeting human Acyl-CoA:cholesterol...