Interferon-γ Drives Treg Fragility to Promote Anti-tumor Immunity

Abigail E Overacre-Delgoffe; Maria Chikina; Rebekah E Dadey; Hiroshi Yano; Erin A Brunazzi; Gulidanna Shayan; William Horne; Jessica M Moskovitz; Jay K Kolls; Cindy Sander; Yongli Shuai; Daniel P Normolle; John M Kirkwood; Robert L Ferris; Greg M Delgoffe; Tullia C Bruno; Creg J Workman; Dario A A Vignali

doi:10.1016/j.cell.2017.05.005

Interferon-γ Drives T_reg Fragility to Promote Anti-tumor Immunity

Cell. 2017 Jun 1;169(6):1130-1141.e11. doi: 10.1016/j.cell.2017.05.005. Epub 2017 May 25.

Authors

Abigail E Overacre-Delgoffe¹, Maria Chikina², Rebekah E Dadey³, Hiroshi Yano³, Erin A Brunazzi³, Gulidanna Shayan⁴, William Horne⁵, Jessica M Moskovitz⁶, Jay K Kolls⁷, Cindy Sander⁸, Yongli Shuai⁹, Daniel P Normolle⁹, John M Kirkwood¹⁰, Robert L Ferris¹¹, Greg M Delgoffe¹², Tullia C Bruno¹³, Creg J Workman¹, Dario A A Vignali¹⁴

Affiliations

¹ 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.
² Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
³ Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
⁴ Tumor Microenvironment Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
⁵ Richard King Mellon Foundation Institute for Pediatric Research, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA.
⁶ 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.
⁷ 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.
⁸ Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USA.
⁹ UPCI Biostatistics Facility, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
¹⁰ 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.
¹¹ 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, Pittsburgh, PA 15213, USA.
¹² 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.
¹³ 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.
¹⁴ 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 address: dvignali@pitt.edu.

Abstract

Regulatory T cells (T_regs) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral T_reg stability and function but is dispensable for peripheral immune tolerance. T_reg-restricted Nrp1 deletion results in profound tumor resistance due to T_reg functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of T_reg fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1⁺ T_regs 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^+/+) T_regs can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1^-/- T_regs produce interferon-γ (IFNγ), which drives the fragility of surrounding wild-type T_regs, boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced T_reg fragility is required for response to anti-PD1, suggesting that cancer therapies promoting T_reg fragility may be efficacious.

Keywords: PD-1; cancer immunotherapy; interferon-γ; interferon-γ receptor; neuropilin-1; regulatory T cells; tumor immunology; tumor microenvironment.

MeSH terms

Animals
Carcinoma, Squamous Cell / immunology*
Female
Forkhead Transcription Factors
Gene Expression Profiling
Gene Regulatory Networks
Head and Neck Neoplasms / immunology*
Humans
Interferon gamma Receptor
Interferon-gamma / immunology*
Male
Melanoma / immunology*
Melanoma, Experimental / immunology
Mice
Mice, Inbred C57BL
Neuropilin-1 / metabolism
Programmed Cell Death 1 Receptor / metabolism
Receptors, Interferon / genetics
Receptors, Interferon / metabolism
T-Lymphocytes, Regulatory / immunology*
Tumor Microenvironment

Substances

Forkhead Transcription Factors
Foxp3 protein, mouse
Programmed Cell Death 1 Receptor
Receptors, Interferon
Neuropilin-1
Interferon-gamma

Abstract

MeSH terms

Substances

Grants and funding