title: The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment.
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.
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA 30912, USA. ; Department of Pediatrics, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Madhav D
authors.initials: MD
authors.lastname: Sharma
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Rahul
authors.initials: R
authors.lastname: Shinde
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA 30912, USA. ; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: McGaha
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA 30912, USA. ; Department of Radiology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Medicine, Immunology Program and Ludwig Center, Memorial Sloan Kettering Cancer Center; Weill Cornell Medical School and Graduate School of Biomedical Sciences; and Ludwig Institute for Cancer Research, New York, NY 10065, USA.
authors.forename: Rikke B
authors.initials: RB
authors.lastname: Holmgaard
authors.affiliation: Department of Medicine, Immunology Program and Ludwig Center, Memorial Sloan Kettering Cancer Center; Weill Cornell Medical School and Graduate School of Biomedical Sciences; and Ludwig Institute for Cancer Research, New York, NY 10065, USA.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: NewLink Genetics Inc., Ames, IA 50010, USA.
authors.forename: Mario R
authors.initials: MR
authors.lastname: Mautino
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA 30912, USA. ; Department of Biochemistry, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.affiliation: Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Loise M
authors.initials: LM
authors.lastname: Francisco
authors.affiliation: Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Powell
authors.affiliation: Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA 30912, USA. ; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: Cancer Center, Georgia Regents University, Augusta, GA 30912, USA. ; Department of Pediatrics, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
keywords: PTEN; Regulatory T cells; Tregs; indoleamine 2,3-dioxygenase; tumor immunology; tumor microenvironment