NR4A transcription factors limit CAR T cell function in solid tumours

Nature
Joyce ChenAnjana Rao

Abstract

T cells expressing chimeric antigen receptors (CAR T cells) targeting human CD19 (hCD19) have shown clinical efficacy against B cell malignancies1,2. CAR T cells have been less effective against solid tumours3-5, in part because they enter a hyporesponsive ('exhausted' or 'dysfunctional') state6-9 triggered by chronic antigen stimulation and characterized by upregulation of inhibitory receptors and loss of effector function. To investigate the function of CAR T cells in solid tumours, we transferred hCD19-reactive CAR T cells into hCD19+ tumour-bearing mice. CD8+CAR+ tumour-infiltrating lymphocytes and CD8+ endogenous tumour-infiltrating lymphocytes expressing the inhibitory receptors PD-1 and TIM3 exhibited similar profiles of gene expression and chromatin accessibility, associated with secondary activation of nuclear receptor transcription factors NR4A1 (also known as NUR77), NR4A2 (NURR1) and NR4A3 (NOR1) by the initiating transcription factor NFAT (nuclear factor of activated T cells)10-12. CD8+ T cells from humans with cancer or chronic viral infections13-15 expressed high levels of NR4A transcription factors and displayed enrichment of NR4A-binding motifs in accessible chromatin regions. CAR T cells lacking all three NR4A...Continue Reading

Associated Clinical Trials

References

Oct 4, 2005·Proceedings of the National Academy of Sciences of the United States of America·Aravind SubramanianJill P Mesirov
Oct 24, 2007·Annual Review of Immunology·Rosanne Spolski, Warren J Leonard
Mar 6, 2009·Genome Biology·Ben LangmeadSteven L Salzberg
Dec 18, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Banafsheh KadkhodaeiThomas Perlmann
Jul 9, 2011·Nature Immunology·E John Wherry
Sep 8, 2012·Nature·UNKNOWN ENCODE Project Consortium
Oct 30, 2012·Bioinformatics·Alexander DobinThomas R Gingeras
Jan 22, 2013·Nature Immunology·Takashi SekiyaAkihiko Yoshimura
Feb 12, 2013·Nature Immunology·J Adam BestUNKNOWN Immunological Genome Project Consortium
Aug 21, 2013·PLoS Computational Biology·Michael LawrenceVincent J Carey
Nov 12, 2013·Trends in Immunology·Andrea Schietinger, Philip D Greenberg
Jan 5, 2014·Nature Protocols·Simone PicelliRickard Sandberg
Feb 21, 2014·Science Translational Medicine·Marco L DavilaRenier Brentjens
Jun 13, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Edmund K MoonSteven M Albelda
Oct 16, 2014·The New England Journal of Medicine·Shannon L MaudeStephan A Grupp
Dec 18, 2014·Genome Biology·Michael I LoveSimon Anders
Jan 22, 2015·Nucleic Acids Research·Matthew E RitchieGordon K Smyth
Feb 15, 2015·Immunity·Gustavo J MartinezAnjana Rao
Mar 25, 2015·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Nabil AhmedStephen Gottschalk
Jun 2, 2015·The New England Journal of Medicine·James LarkinJedd D Wolchok
Oct 30, 2016·Science·Debattama R SenW Nicholas Haining
Mar 12, 2017·Proceedings of the National Academy of Sciences of the United States of America·Giuliana P MognolSara Trifari
May 18, 2017·Nature·Mary PhilipAndrea Schietinger
Dec 7, 2017·Nature·J Justin MilnerAnanda W Goldrath

❮ Previous
Next ❯

Citations

Jun 4, 2019·Proceedings of the National Academy of Sciences of the United States of America·Hyungseok SeoAnjana Rao
Aug 21, 2019·Nature Immunology·Thomas H Mann, Susan M Kaech
Oct 5, 2019·Nature·Alexandre P BénéchetMatteo Iannacone
Nov 15, 2019·The Journal of Biological Chemistry·Longying JiangYongheng Chen
Dec 6, 2019·Nature·Rachel C LynnCrystal L Mackall
Oct 9, 2019·Nature Reviews. Immunology·Axel KalliesDaniel T Utzschneider
Sep 6, 2019·Science Translational Medicine·Ji LiTeemu T Junttila
Mar 19, 2020·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·Dawei ZouWenhao Chen
Mar 30, 2020·The Journal of Immunology : Official Journal of the American Association of Immunologists·Zhen ZhangYi Zhang
Feb 6, 2020·Annual Review of Immunology·Adrian C Hayday, Pierre Vantourout
Feb 19, 2020·The Journal of Clinical Investigation·Sonia GuedanAvery D Posey
May 21, 2020·Cellular & Molecular Immunology·Iñaki EtxeberriaIgnacio Melero
Dec 18, 2019·Briefings in Functional Genomics·Guillermo Ureña-BailénMarkus Mezger
May 31, 2020·International Journal of Molecular Sciences·Hagma H WorkelMarco de Bruyn
Sep 24, 2020·Immunological Reviews·Chirine RafiaEmmanuel Scotet
Oct 2, 2019·Nature Reviews. Immunology·Christian U BlankDietmar Zehn
Apr 3, 2019·Nature Reviews. Cancer·Alexandra Flemming
Aug 29, 2019·Proceedings of the National Academy of Sciences of the United States of America·Judith F AshouriArthur Weiss
Feb 13, 2020·Current Oncology Reports·Christopher G TwittyAdil I Daud
Jul 14, 2020·ELife·Nathan E Reticker-Flynn, Edgar G Engleman
Jul 14, 2020·Current Opinion in Oncology·Fabian FreitagMichael Hudecek
Jul 9, 2020·Frontiers in Immunology·Xianhui MengJie Sun
Jul 31, 2020·Proceedings of the National Academy of Sciences of the United States of America·Chang LiuHongyan Wang
Aug 23, 2020·Cancers·Didem SakaHande Asimgil
Apr 3, 2019·Signal Transduction and Targeted Therapy·Feng Li, Yi Zhang
Jul 30, 2019·The Keio Journal of Medicine·Ryota SakaiMinako Ito
Jul 10, 2019·The Journal of Immunology : Official Journal of the American Association of Immunologists·Adrian C Hayday
Nov 7, 2019·The Journal of Experimental Medicine·Alvin PratamaChristophe Benoist
Oct 22, 2019·Immunological Reviews·Corey TanJulie Zikherman
Mar 13, 2019·Nature Reviews. Immunology·Alexandra Flemming
Mar 12, 2020·Immune Network·Se Jin Im, Sang-Jun Ha
Nov 5, 2019·Frontiers in Immunology·Lijun Zhao, Yu J Cao
May 20, 2020·Journal of Hematology & Oncology·Yonggui TianYi Zhang
Sep 23, 2020·Nature Metabolism·Fabien FrancoPing-Chih Ho
Jul 3, 2020·Proceedings of the National Academy of Sciences of the United States of America·Amrendra KumarSebastian Joyce

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Methods Mentioned

BETA
PMA
flow cytometry
RNA-seq
immunoprecipitation
PCR
Transfection
FACS
ChIP

Software Mentioned

R
Bioconductor
Java Genomics Toolkit
MEDIPS
limma
Illumina Basespace
MACS2
GraphPad
samtools
DESeq2

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