Muth et al. showed in mixed bone marrow chimeric mice engineered to temporally deplete part of the Treg cell compartment, that just 20% of the Treg population was sufficient to maintain CD8+ T cell peripheral tolerance. Selective elimination of CD27, a T cell costimulatory receptor, on the remaining Tregs boosted CD8+ T cell expansion in response to LCMV-peptide antigen immunization and antitumor activity against established s.c. MC38 colon adenocarcinomas. PD-1 blockade strongly synergized with CD27 ablation on Tregs to boost levels and effector functions of intratumoral CD8+ T cells. Tumor control was abolished by depletion of CD8+ T cells.
Contributed by Paula Hochman
ABSTRACT: Regulatory T cells (Tregs) suppress immune responses and thus contribute to immune homeostasis. On the downside, Tregs also limit immune responses against tumors promoting the progression of cancer. Among the many mechanisms implied in Treg-mediated suppression, the inhibition of dendritic cells (DCs) has been shown to be central in peripheral tolerance induction as well as in cancers. We have shown previously that the maintenance of peripheral T cell tolerance critically depends on cognate interactions between Tregs and DCs and that the CTL priming by unsuppressed steady state DCs is mediated via CD70. Here, we have investigated whether the CD70/CD27 axis is also involved in Treg-mediated suppression of anti-tumor immunity. Using a mixed bone marrow chimeric mouse model in which we can deplete regulatory T cells in a temporally controlled fashion, we show that Treg-expressed CD27 prevents the breakdown of peripheral tolerance and limits anti-tumor immunity. Furthermore, ablation of Treg expressed CD27 acts synergistically with PD-1 checkpoint inhibition to improve CTL mediated immunity against a solid tumor. Our data thus identify Treg-expressed CD27 as a potential target in cancer immunotherapy. KEY MESSAGES : Treg expressed CD27 maintains steady state DC tolerogenic Treg expressed CD27 limits anti-tumor immunity Ablation of Treg expressed CD27 synergizes with PD-1 blockade to improve CTL mediated tumor control.