Interferon-γ Drives T_reg 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-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.