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The PTEN pathway in Tregs is a critical driver for the suppressive tumor microenvironment

Lookup NU author(s): Dr Lei Huang, Emeritus Professor Andrew Mellor

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Abstract

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.


Publication metadata

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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