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

Abstract

Summary Regulatory T cells (Tregs) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral Treg stability and function but is dispensable for peripheral immune tolerance. Treg-restricted Nrp1 deletion results in profound tumor resistance due to Treg functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of Treg fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1+ Tregs 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+/+) Tregs can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1−/− Tregs produce interferon-γ (IFNγ), which drives the fragility of surrounding WT Tregs, boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced Treg fragility is required for response to anti-PD1, suggesting that cancer therapies promoting Treg fragility may be efficacious.

Regulatory T cell features in chronic granulomatous disease

“…The reduction in eT reg cell numbers in (gp91 phox -deficient) CGD patients is consistent with diminished induction of such cells due to lack of ROS produced by macrophages or with the destabilization of T regs as a consequence of the presence of inflammatory cytokines, as suggested previously [23]. The reduction in eT reg cell numbers in (gp91 phox -deficient) CGD patients is consistent with diminished induction of such cells due to lack of ROS produced by macrophages or with the destabilization of T regs as a consequence of the presence of inflammatory cytokines, as suggested previously [23].…”

High self-reactivity drives T-bet and potentiates Treg function in tissue-specific autoimmunity

“…It was recently demonstrated that Treg-specific deletion of T-bet abrogated the ability of Tregs to prevent autoimmune diabetes in NOD mice (32). On the other hand, under some circumstances, T-bet -and subsequently IFNγ -expression can lead to Treg instability (48,(64)(65)(66). Thus, it remains unclear whether sustained antigen exposure, and consequently continuous TCR signaling, lead to T-bet expression and subsequent Treg destabilization.…”

Interferon gamma in cancer immunotherapy

“…Tregs permit tumor growth and are a barrier in an effective antitumor immune response. Neuropilin‐1 (Nrp1), a trans‐membrane molecule, is needed to maintain the stability and function of tumor‐infiltrating Tregs but is dispensable for peripheral Tregs . Overacre‐Delgoffe et al recently found that a high frequency of Nrp1 −/− Tregs in the tumors produce IFNγ, which suppress surrounding WT Tregs in the tumor and in turn facilitated tumor elimination.…”