In vivo discovery of immunotherapy targets in the tumour microenvironment

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 and Kai W. Wucherpfennig ()
Additional contact information
Penghui Zhou: Dana-Farber Cancer Institute
Donald R. Shaffer: Dana-Farber Cancer Institute
Diana A. Alvarez Arias: Dana-Farber Cancer Institute
Yukoh Nakazaki: Dana-Farber Cancer Institute
Wouter Pos: Dana-Farber Cancer Institute
Alexis J. Torres: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Viviana Cremasco: Dana-Farber Cancer Institute
Stephanie K. Dougan: Whitehead Institute, Massachusetts Institute of Technology
Glenn S. Cowley: Broad Institute of MIT and Harvard
Kutlu Elpek: Dana-Farber Cancer Institute
Jennifer Brogdon: Novartis Institutes for Biomedical Research
John Lamb: Genomics Institute of the Novartis Research Foundation
Shannon J. Turley: Dana-Farber Cancer Institute
Hidde L. Ploegh: Whitehead Institute, Massachusetts Institute of Technology
David E. Root: Broad Institute of MIT and Harvard
J. Christopher Love: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology
Glenn Dranoff: Dana-Farber Cancer Institute
Nir Hacohen: Broad Institute of MIT and Harvard
Harvey Cantor: Dana-Farber Cancer Institute
Kai W. Wucherpfennig: Dana-Farber Cancer Institute

Nature, 2014, vol. 506, issue 7486, 52-57

Abstract: 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.

Date: 2014
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DOI: 10.1038/nature12988

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