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Interferon-γ Drives Treg Fragility to Promote Anti-tumor Immunity.
Overacre-Delgoffe, Abigail E; Chikina, Maria; Dadey, Rebekah E; Yano, Hiroshi; Brunazzi, Erin A; Shayan, Gulidanna; Horne, William; Moskovitz, Jessica M; Kolls, Jay K; Sander, Cindy; Shuai, Yongli; Normolle, Daniel P; Kirkwood, John M; Ferris, Robert L; Delgoffe, Greg M; Bruno, Tullia C; Workman, Creg J; Vignali, Dario A A.
Affiliation
  • Overacre-Delgoffe AE; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • Chikina M; Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
  • Dadey RE; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
  • Yano H; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
  • Brunazzi EA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
  • Shayan G; Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
  • Horne W; Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA.
  • Moskovitz JM; Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA; Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
  • Kolls JK; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA.
  • Sander C; Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.
  • Shuai Y; UPCI Biostatistics Facility, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
  • Normolle DP; UPCI Biostatistics Facility, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
  • Kirkwood JM; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.
  • Ferris RL; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA; Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute,
  • Delgoffe GM; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
  • Bruno TC; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
  • Workman CJ; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
  • Vignali DAA; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA. Electronic a
Cell ; 169(6): 1130-1141.e11, 2017 Jun 01.
Article in En | MEDLINE | ID: mdl-28552348
ABSTRACT
Regulatory T cells (Tregs) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral Treg stability and function but is dispensable for peripheral immune tolerance. Treg-restricted Nrp1 deletion results in profound tumor resistance due to Treg functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of Treg fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1+ Tregs correlates with poor prognosis in melanoma and head and neck squamous cell carcinoma. Using a mouse model of melanoma where Nrp1-deficient (Nrp1-/-) and wild-type (Nrp1+/+) Tregs can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1-/- Tregs produce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type Tregs, boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced Treg fragility is required for response to anti-PD1, suggesting that cancer therapies promoting Treg fragility may be efficacious.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Squamous Cell / Interferon-gamma / T-Lymphocytes, Regulatory / Head and Neck Neoplasms / Melanoma Type of study: Prognostic_studies Limits: Animals / Female / Humans / Male Language: En Journal: Cell Year: 2017 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Carcinoma, Squamous Cell / Interferon-gamma / T-Lymphocytes, Regulatory / Head and Neck Neoplasms / Melanoma Type of study: Prognostic_studies Limits: Animals / Female / Humans / Male Language: En Journal: Cell Year: 2017 Type: Article Affiliation country: United States