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.

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.

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 / 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
  • interferon gamma receptor
  • Neuropilin-1
  • Interferon-gamma