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

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-gamma (IFN gamma), which drives the fragility of surrounding wild-type T-regs, boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFN gamma-induced T-reg fragility is required for response to anti-PD1, suggesting that cancer therapies promoting T-reg fragility may be efficacious.