NRP Treg–derived IFNγ is a critical mediator of FOXP3+ Treg functional fragility.

  • Major finding: NRP Treg–derived IFNγ is a critical mediator of FOXP3+ Treg functional fragility.

  • Approach: Mouse models with NRP Tregs, NRP+ Tregs, or an equal ratio of NRP and NRP+ Tregs were evaluated.

  • Impact: Targeting NRP+ Treg fragility may improve the efficacy of antitumor immunotherapy.


Although regulatory T cells (Treg), which are a subpopulation of CD4+ T cells that express the transcription factor FOXP3, maintain immune homeostasis by suppressing effector T cells to prevent immune responses against self-antigens, they also impair antitumor immunity. Having shown that neuropilin 1 (NRP1) was essential for intratumoral Treg function and survival in mice and that NRP1FOXP3+ Tregs were dysfunctional, Overacre-Delgoffe and colleagues sought to further elucidate the role of NRP1FOXP3+ Tregs in antitumor immunity. Elevated intratumoral NRP1+ Tregs were found in patients with metastatic melanoma or head and neck squamous cell carcinoma, and were also correlated with poor prognosis for these patients. Mice with either NRP1 FOXP3+ Tregs (Nrp1L/LFoxp3Cre−YFP/Cre−YFP) or an equal ratio of NRP1 FOXP3+ and wild-type (WT) Tregs (Nrp1L/LFoxp3Cre−YFP/DTR−GFP) exhibited reduced melanoma growth, elevated levels of tumor-infiltrating lymphocytes (TIL), and increased survival compared to mice with WT Tregs. NRP1 FOXP3+ Tregs from Nrp1L/LFoxp3Cre−YFP/Cre−YFP and both NRP1 FOXP3+ Tregs and WT Tregs from Nrp1L/LFoxp3Cre−YFP/DTR−GFP mice did not exhibit immunosuppressive activity, and exhibited increased expression of genes associated with IFNg/IL12 signaling, cell-surface expression of IFNg receptor (IFNgR), and increased IFNg expression. Further, Tregs comprised the majority of IFNg+ TILs in Nrp1L/LFoxp3Cre−YFP/Cre−YFP and Nrp1L/LFoxp3Cre−YFP/DTR−GFP mice, and antitumor responses were dependent upon the presence of IFNg+ NRP1 FOXP3+ Tregs but not IFNg+ CD8+ T cells. HIF1a was elevated in Nrp1−/− Tregs compared to Nrp1+/+ Tregs, and WT Tregs cultured under hypoxic conditions exhibited increased expression of IFNg and HIF1a, suggesting that hypoxia may induce Treg dysfunction via HIF1a. Nrp1−/− Treg–derived IFNg promoted the dysfunction of Nrp1+/+ Tregs both in vitro and in vivo. Lastly, IFNγ-induced Treg fragility is required for response to anti–PD-1 checkpoint blockade in vivo. These results describe how NRP1 FOXP3+ Tregs drive Treg dysfunction and identify potential approaches to enhance antitumor immunotherapy.

Overacre-Delgoffe AE, Chikina M, Dadey RE, Yano H, Brunazzi EA, Shayan G, et al. Interferonγ drives Treg fragility to promote anti-tumor immunity. Cell 2017;169:1130–41.e11.

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