Volume 3 Supplement 2

30th Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2015)

Open Access

The PTEN pathway in Tregs functions as a critical driver of the immunosuppressive tumor microenvironment and tolerance to apoptotic cells

  • Madhav Sharma1,
  • Rahul Shinde1,
  • Tracy McGaha1,
  • Lei Huang1,
  • Rikke Holmgaard2,
  • Jedd Wolchok2,
  • Mario Mautino3,
  • Esteban Celis1,
  • Arlene Sharpe4,
  • Loise Francisco4,
  • Jonathan Powell5,
  • Hideo Yagita6,
  • Andrew Mellor1,
  • Bruce Blazar7 and
  • David Munn8
Journal for ImmunoTherapy of Cancer20153(Suppl 2):O19

DOI: 10.1186/2051-1426-3-S2-O19

Published: 4 November 2015

The tumor microenvironment is profoundly immunosuppressive, but exactly how this is coordinated and maintained remains poorly understood. We show that multiple transplantable and autochthonous mouse tumors actively elicit a population of highly suppressive regulatory T cells (Tregs) expressing the lipid phosphatase PTEN. These PTEN+ Tregs co-expressed PD-1, Foxp3, and high levels of Eos (Ikzf4). PTEN signaling acted to stabilize tumor-associated Tregs, maintaining their suppressor activity and preventing conversion into pro-inflammatory effector cells (“ex-Tregs”) in the face of inflammation. Mice with a targeted deletion of PTEN in Tregs (PTEN-Treg-KO mice) were healthy and fertile when young, but gradually developed lupus-like autoimmunity as they aged. Tumors implanted in young, healthy PTEN-Treg-KO mice were unable to create the normal immunosuppressive tumor microenvironment; instead, tumors were constitutively immunogenic, chronically inflamed, and could barely grow. In wild-type mice with large, pre-established tumors, pharmacologic inhibition of PTEN during the period following chemotherapy or adoptive immunotherapy caused a profound reconfiguration of the tumor microenvironment. The normally suppressive intratumoral Tregs became destabilized, and rapidly reprogrammed into pro-inflammatory “ex-Tregs” expressing IL-2, IL-17 and CD40L. The dominant APCs in the tumor changed from tolerogenic DCs expressing high levels of PD-L1, and were replaced by inflammatory myeloid DCs expressing high levels of CD86, MHC class II, IL-6 and IL-12. CD8+ effector T cells in the tumor, which had previously been unresponsive and PD-1+ (exhausted), became activated and expressed IFNγ and GzmB, and mediated tumor regression. Pharmacologic inhibition of PTEN was highly synergistic with conventional chemotherapy, allowing a single modest, normally ineffective dose of chemotherapy to trigger rapid tumor involution. This synergy was strictly immune-mediated, and was lost in the absence of host CD8+ T cells. In mice without tumors, identical PTEN+ Tregs were physiologically elicited by exposure to apoptotic cells; and PTEN-Treg-KO mice rapidly developed lupus-like autoimmunity when repeatedly challenged with apoptotic cells. The induction of PTEN+ Tregs by apoptotic cells was driven by indoleamine 2,3-dioxygenase (IDO) in the host, and was blocked by pharmacologic inhibition of IDO. Taken together, these data identify the PTEN pathway in Tregs as a potent immunosuppressive mechanism in tumors. PTEN+ Tregs controlled the downstream activation of inflammatory DCs and effector CD8+ T cells, and were part of the fundamental mechanism of tolerance to apoptotic cells. The PTEN pathway thus represents a potent, centrally-positioned immunosuppressive mechanism in tumors, which is amenable to pharmacologic inhibition and shows synergy with both adoptive immunotherapy and conventional chemotherapy.

Authors’ Affiliations

(1)
Georgia Regents University
(2)
Memorial Sloan-Kettering Cancer Center
(3)
NewLink Genetics, Inc.
(4)
Harvard Medical School
(5)
Johns Hopkins University School of Medicine
(6)
Juntendo University School of Medicine
(7)
University of Minnesota
(8)
Georgia Regents University Cancer Center

Copyright

© Sharma et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Advertisement