Interferon-γ drives T reg fragility to promote anti-tumor immunity

Regulatory T cells (Tregs) are a barrier to effective anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral Treg stability and function but is dispensable for peripheral immune homeostasis, Treg-restricted Nrp1 deletion in mice results in profound tumor resistant due to Treg functional fragility. Drivers of Treg fragility, the mechanistic basis of Nrp1 dependency, and the relevance of these processes for human cancer and immunotherapy remain unknown. NRP1 expression on human Tregs in melanoma and HNSCC was highly heterogeneous and correlated with prognosis. Using a mouse model of melanoma in which mutant Nrp1-deficient (Nrp1–/–) and wild type (WT) Tregs could be assessed in a competitive environment, we found that a high proportion of intratumoral Nrp1–/– Tregs produce interferon-γ (IFNγ), which in turn drove the fragility of surrounding WT Tregs, boosting anti-tumor immunity and facilitating tumor clearance. We also show that IFNγ-induced Treg fragility is required for an effective response to PD1 immunotherapy, suggesting that cancer therapies promoting Treg fragility may be efficacious .