抗 PD-1 检查点治疗可促进调节性 T 细胞的功能和存活

We have previously shown in a model of claudin-low breast cancer that regulatory T cells (T regs ) are increased in the tumor microenvironment (TME) and express high levels of PD-1. In mouse models and patients with triple-negative breast cancer, it is postulated that one cause for the lack of activity of anti-PD-1 therapy is the activation of PD-1-expressing T regs in the TME.

We hypothesized that the expression of PD-1 on T regs would lead to enhanced suppressive function of T regs and worsen antitumor immunity during PD-1 blockade. To evaluate this, we isolated T regs from claudin-low tumors and functionally evaluated them ex vivo.

We compared transcriptional profiles of T regs isolated from tumor-bearing mice with or without anti-PD-1 therapy using RNA sequencing.

We found several genes associated with survival and proliferation pathways; for example, Jun , Fos, and Bcl2 were significantly upregulated in T regs exposed to anti-PD-1 treatment. Based on these data, we hypothesized that anti-PD-1 treatment on T regs results in a prosurvival phenotype. Indeed, T regs exposed to PD-1 blockade had significantly higher levels of Bcl-2 expression, and this led to increased protection from glucocorticoid-induced apoptosis.

In addition, we found in vitro and in vivo that T regs in the presence of anti-PD-1 proliferated more than control T regs PD-1 blockade significantly increased the suppressive activity of T regs at biologically relevant T reg /T naive cell ratios. Altogether, we show that this immunotherapy blockade increases proliferation, protection from apoptosis, and suppressive capabilities of T regs , thus leading to enhanced immunosuppression in the TME.