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Anti-PD-1 Checkpoint Therapy Can Promote the Function and Survival of Regulatory T Cells.


ABSTRACT: We have previously shown in a model of claudin-low breast cancer that regulatory T cells (Tregs) 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 Tregs in the TME. We hypothesized that the expression of PD-1 on Tregs would lead to enhanced suppressive function of Tregs and worsen antitumor immunity during PD-1 blockade. To evaluate this, we isolated Tregs from claudin-low tumors and functionally evaluated them ex vivo. We compared transcriptional profiles of Tregs 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 Tregs exposed to anti-PD-1 treatment. Based on these data, we hypothesized that anti-PD-1 treatment on Tregs results in a prosurvival phenotype. Indeed, Tregs 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 Tregs in the presence of anti-PD-1 proliferated more than control Tregs PD-1 blockade significantly increased the suppressive activity of Tregs at biologically relevant Treg/Tnaive cell ratios. Altogether, we show that this immunotherapy blockade increases proliferation, protection from apoptosis, and suppressive capabilities of Tregs, thus leading to enhanced immunosuppression in the TME.

SUBMITTER: Vick SC 

PROVIDER: S-EPMC8578393 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Anti-PD-1 Checkpoint Therapy Can Promote the Function and Survival of Regulatory T Cells.

Vick Sarah C SC   Kolupaev Oleg V OV   Perou Charles M CM   Serody Jonathan S JS  

Journal of immunology (Baltimore, Md. : 1950) 20211004 10


We have previously shown in a model of claudin-low breast cancer that regulatory T cells (T<sub>regs</sub>) 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<sub>regs</sub> in the TME. We hypothesized that the expression of PD-1 on T<sub>regs</sub> would lead to enhanced suppressive f  ...[more]

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