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Nature. 2014 Feb 6;506(7486):52-7. doi: 10.1038/nature12988. Epub 2014 Jan 29.

In vivo discovery of immunotherapy targets in the tumour microenvironment.

Author information

1
1] Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2].
2
1] Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] [3] Jounce Therapeutics, Cambridge, Massachusetts 02138, USA.
3
Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
4
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
5
Whitehead Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
6
Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
7
1] Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Jounce Therapeutics, Cambridge, Massachusetts 02138, USA.
8
Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139, USA.
9
Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.

Abstract

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.

PMID:
24476824
PMCID:
PMC4052214
DOI:
10.1038/nature12988
[Indexed for MEDLINE]
Free PMC Article

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