免疫疗法是癌症研究的一个重要领域，而且最新研究表明，以T细胞上的抑制性受体为目标进行治疗，在临床上对晚期癌症患者会有好处。这一领域的一个主要问题是，难以找到潜在治疗目标。

       在这项研究中，Kai Wucherpfennig及同事证明，在活体中寻找治疗目标是可行的：利用“短发卡RNA”(shRNA)筛选来识别在长有肿瘤的小鼠体内改变能渗透进肿瘤的CD8 T细胞之作用的基因。他们识别出调控性磷酸脂酶Ppp2r2d是这样一个目标，并且发现T细胞中Ppp2r2d的抑制使它们能在肿瘤内积累，同时显著延迟肿瘤生长。

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  & Kai W. Wucherpfennig

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.