In vivo discovery of immunotherapy targets in the tumour microenvironment

被引：193

作者：

Zhou, Penghui ^{[1
]}

Shaffer, Donald R. ^{[1
]}

Arias, Diana A. Alvarez ^{[1
]}

Nakazaki, Yukoh ^{[1
]}

Pos, Wouter ^{[1
]}

Torres, Alexis J. ^{[2
]}

Cremasco, Viviana ^{[1
]}

Dougan, Stephanie K. ^{[3
]}

Cowley, Glenn S. ^{[4
]}

Elpek, Kutlu ^{[1
]}

Brogdon, Jennifer ^{[5
]}

Lamb, John ^{[6
]}

Turley, Shannon J. ^{[1
]}

Ploegh, Hidde L. ^{[3
]}

Root, David E. ^{[4
]}

Love, J. Christopher ^{[2
]}

Dranoff, Glenn ^{[1
]}

Hacohen, Nir ^{[4
]}

Cantor, Harvey ^{[1
]}

Wucherpfennig, Kai W. ^{[1
]}

机构：

[1] Dana Farber Canc Inst, Boston, MA 02115 USA

[2] MIT, David H Koch Inst Integrat Canc Res, Cambridge, MA 02142 USA

[3] MIT, Whitehead Inst, Cambridge, MA 02142 USA

[4] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] Novartis Inst Biomed Res, Cambridge, MA 02139 USA

[6] Novartis Res Fdn, Genom Inst, San Diego, CA 92121 USA

来源：

NATURE | 2014年 / 506卷 / 7486期

基金：

美国国家卫生研究院;

关键词：

CD8+ T-CELLS; PROGNOSTIC-FACTORS; IMMUNE CELLS; CANCER; MELANOMA; PHOSPHATASE; SUPPRESSORS; LYMPHOCYTES; PROTEINS; SURVIVAL;

D O I：

10.1038/nature12988

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：52 / +

页数：15

共 48 条

[1] Gene Sets Identified with Oncogene Cooperativity Analysis Regulate In Vivo Growth and Survival of Leukemia Stem Cells [J].