Format

Send to

Choose Destination
Sci Adv. 2015 Nov 6;1(10):e1500845. doi: 10.1126/sciadv.1500845. eCollection 2015 Nov.

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

Author information

1
Cancer Center, Georgia Regents University, Augusta, GA 30912, USA. ; Department of Pediatrics, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
2
Cancer Center, Georgia Regents University, Augusta, GA 30912, USA.
3
Cancer Center, Georgia Regents University, Augusta, GA 30912, USA. ; Department of Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
4
Cancer Center, Georgia Regents University, Augusta, GA 30912, USA. ; Department of Radiology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
5
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.
6
NewLink Genetics Inc., Ames, IA 50010, USA.
7
Cancer Center, Georgia Regents University, Augusta, GA 30912, USA. ; Department of Biochemistry, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912, USA.
8
Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.
9
Sidney Kimmel Comprehensive Cancer Research Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
10
Department of Immunology, Juntendo University School of Medicine, Bunkyo-ku, Tokyo 113-8421, Japan.
11
Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA.

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.

KEYWORDS:

PTEN; Regulatory T cells; Tregs; indoleamine 2,3-dioxygenase; tumor immunology; tumor microenvironment

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center