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Lookup NU author(s): Dr Lei HuangORCiD, Emeritus Professor Andrew MellorORCiD
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
The tumor microenvironment is profoundly immunosuppressive. We show that multiple tumor types create intratumoral immune suppression driven by a specialized form of regulatory T cell (Treg) activation dependent on the PTEN (phosphatase and tensin homolog) lipid phosphatase. PTEN acted to stabilize Tregs in tumors, preventing them from reprogramming into inflammatory effector cells. In mice with a Treg-specific deletion of PTEN, tumors grew slowly, were inflamed, and could not create an immunosuppressive tumor microenvironment. In normal mice, exposure to apoptotic tumor cells rapidly elicited PTEN-expressing Tregs, and PTEN-deficient mice were unable to maintain tolerance to apoptotic cells. In wild-type mice with large established tumors, pharmacologic inhibition of PTEN after chemotherapy or immunotherapy profoundly reconfigured the tumor microenvironment, changing it from a suppressive to an inflammatory milieu, and tumors underwent rapid regression. Thus, the immunosuppressive milieu in tumors must be actively maintained, and tumors become susceptible to immune attack if the PTEN pathway in Tregs is disrupted.
Author(s): Sharma MD, Shinde R, McGaha TL, Huang L, Holmgaard RB, Wolchok JD, Mautino MR, Celis E, Sharpe AH, Francisco LM, Yagita H, Mellor AL, Blazar BR, Munn DH
Publication type: Article
Publication status: Published
Journal: Science Advances
Year: 2015
Volume: 1
Issue: 10
Online publication date: 06/11/2015
Acceptance date: 14/08/2015
Date deposited: 06/01/2016
ISSN (electronic): 2375-2548
Publisher: American Association for the Advancement of Science
URL: http://dx.doi.org/10.1126/sciadv.1500845
DOI: 10.1126/sciadv.1500845
PubMed id: 26601142
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