IFNγ Induces FOXP3⁺ Treg Dysfunction to Promote Antitumor Immunity

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 NRP1⁻FOXP3⁺ Tregs were dysfunctional, Overacre-Delgoffe and colleagues sought to further elucidate the role of NRP1⁻FOXP3⁺ 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 (Nrp1^L/LFoxp3^{Cre−YFP/Cre−YFP}) or an equal ratio of NRP1⁻ FOXP3⁺ and wild-type (WT) Tregs (Nrp1^L/LFoxp3^{Cre−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 Nrp1^L/LFoxp3^{Cre−YFP/Cre−YFP} and both NRP1⁻ FOXP3⁺ Tregs and WT Tregs from Nrp1^L/L Foxp3^{Cre−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 Nrp1^L/LFoxp3^{Cre−YFP/Cre−YFP} and Nrp1^L/LFoxp3^{Cre−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 T_reg fragility to promote anti-tumor immunity. Cell 2017;169:1130–41.e11.

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