Document Detail


In vivo discovery of immunotherapy targets in the tumour microenvironment.
MedLine Citation:
PMID:  24476824     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Recent clinical trials showed that targeting of inhibitory receptors on T cells induces durable responses in a subset of cancer patients, despite advanced disease. However, the regulatory switches controlling T-cell function in immunosuppressive tumours are not well understood. Here we show that such inhibitory mechanisms can be systematically discovered in the tumour microenvironment. We devised an in vivo pooled short hairpin RNA (shRNA) screen in which shRNAs targeting negative regulators became highly enriched in murine tumours by releasing a block on T-cell proliferation upon tumour antigen recognition. Such shRNAs were identified by deep sequencing of the shRNA cassette from T cells infiltrating tumour or control tissues. One of the target genes was Ppp2r2d, a regulatory subunit of the PP2A phosphatase family. In tumours, Ppp2r2d knockdown inhibited T-cell apoptosis and enhanced T-cell proliferation as well as cytokine production. Key regulators of immune function can therefore be discovered in relevant tissue microenvironments.
Authors:
Penghui Zhou; Donald R Shaffer; Diana A Alvarez Arias; Yukoh Nakazaki; Wouter Pos; Alexis J Torres; Viviana Cremasco; Stephanie K Dougan; Glenn S Cowley; Kutlu Elpek; Jennifer Brogdon; John Lamb; Shannon J Turley; Hidde L Ploegh; David E Root; J Christopher Love; Glenn Dranoff; Nir Hacohen; Harvey Cantor; Kai W Wucherpfennig
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2014-01-29
Journal Detail:
Title:  Nature     Volume:  506     ISSN:  1476-4687     ISO Abbreviation:  Nature     Publication Date:  2014 Feb 
Date Detail:
Created Date:  2014-02-06     Completed Date:  2014-02-18     Revised Date:  2014-10-19    
Medline Journal Info:
Nlm Unique ID:  0410462     Medline TA:  Nature     Country:  England    
Other Details:
Languages:  eng     Pagination:  52-7     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
GEO/GSE53388
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MeSH Terms
Descriptor/Qualifier:
Animals
Antigens, Neoplasm / immunology
Apoptosis / immunology
CD4-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / cytology,  immunology,  secretion
Cell Proliferation
Cytokines / immunology,  secretion
Female
Gene Knockdown Techniques
High-Throughput Nucleotide Sequencing
Immunotherapy* / methods
Lymphocytes, Tumor-Infiltrating / cytology,  immunology,  metabolism,  secretion
Melanoma, Experimental / immunology
Mice
Mice, Inbred C57BL
Molecular Targeted Therapy*
Protein Phosphatase 2 / deficiency,  genetics,  metabolism*
RNA, Small Interfering / genetics
Reproducibility of Results
Tumor Microenvironment / immunology*
Grant Support
ID/Acronym/Agency:
1R01CA173750/CA/NCI NIH HHS; DP3 DK097681/DK/NIDDK NIH HHS; P01 AI045757/AI/NIAID NIH HHS; P30 CA014051/CA/NCI NIH HHS; P30-CA14051/CA/NCI NIH HHS; R01 CA173750/CA/NCI NIH HHS; T32 AI007386/AI/NIAID NIH HHS; T32 AI07386/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, Neoplasm; 0/Cytokines; 0/RNA, Small Interfering; EC 3.1.3.16/Ppp2r2d protein, mouse; EC 3.1.3.16/Protein Phosphatase 2
Comments/Corrections
Comment In:
Nat Rev Drug Discov. 2014 Apr;13(4):258   [PMID:  24658309 ]
Nature. 2014 Feb 6;506(7486):39-40   [PMID:  24476819 ]

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