In vivo discovery of immunotherapy targets in the tumour microenvironment
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 suc...
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Published in | Nature (London) Vol. 506; no. 7486; pp. 52 - 57 |
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Main Authors | , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Nature Publishing Group UK
06.02.2014
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
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Summary: | 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.
A short hairpin RNA screen to identify genes that modify the action of tumour-infiltrating CD8 T cells in tumour-bearing mice pinpointed the phosphatase subunit Ppp2r2d as a new target for tumour therapy; knockdown of
Ppp2r2d
in T cells enabled their accumulation in tumours and significantly delayed tumour growth.
New targets for cancer immunotherapy
Immunotherapy is an important area of cancer research, and recent work has shown that targeting inhibitory receptors on T cells can result in clinical benefit in patients with advanced cancers. A major problem in the field is the difficulty of finding potential targets. Here Kai Wucherpfennig and colleagues show that
in vivo
discovery of therapeutic targets is a practical proposition by using short hairpin RNA (shRNA) screening to identify genes that modify the action of tumour-infiltrating CD8 T cells in tumour-bearing mice. They identify the regulatory phosphatase Ppp2r2d as a target and show that knockdown of
Ppp2r2d
in T cells enabled their accumulation in tumours and significantly delayed tumour growth. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally |
ISSN: | 0028-0836 1476-4687 |
DOI: | 10.1038/nature12988 |