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The PTEN pathway in Tregs functions as a critical driver of the immunosuppressive tumor microenvironment and tolerance to apoptotic cells
  1. Madhav Sharma1,
  2. Rahul Shinde1,
  3. Tracy McGaha1,
  4. Lei Huang1,
  5. Rikke Holmgaard2,
  6. Jedd Wolchok2,
  7. Mario Mautino3,
  8. Esteban Celis1,
  9. Arlene Sharpe4,
  10. Loise Francisco4,
  11. Jonathan Powell5,
  12. Hideo Yagita6,
  13. Andrew Mellor1,
  14. Bruce Blazar7 and
  15. David Munn8
  1. Aff1 grid.410427.40000000419370183Georgia Regents University Augusta GA USA
  2. Aff2 grid.51462.340000000121719952Memorial Sloan-Kettering Cancer Center New York NY USA
  3. Aff3 grid.426927.cNewLink Genetics, Inc. Ames IA USA
  4. Aff4 grid.38142.3c000000041936754XHarvard Medical School Boston MA USA
  5. Aff5 grid.21107.350000000121719311Johns Hopkins University School of Medicine Baltimore MD USA
  6. Aff6 grid.258269.20000000417622738Juntendo University School of Medicine Tokyo Japan
  7. Aff7 grid.17635.360000000419368657University of Minnesota Minneapolis MN USA
  8. Aff8 grid.410427.40000000419370183Georgia Regents University Cancer Center Augusta GA USA

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Meeting abstracts

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.