Elsevier

Clinical Immunology

Volume 168, July 2016, Pages 47-54
Clinical Immunology

Differential effects of inhibitors of the PI3K/mTOR pathway on the expansion and functionality of regulatory T cells

https://doi.org/10.1016/j.clim.2016.05.005Get rights and content
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Highlights

  • Single mTOR and dual PI3K/mTOR inhibitors support a relative Treg expansion benefit.

  • Single mTOR and dual PI3K/mTOR inhibitors promote Treg immunosuppressive activity.

  • Single PI3K inhibition results in similar expansion rates of Tregs and Tconv.

  • The suppressive activity of Tregs is not altered upon culture with PI3K inhibitors.

Abstract

The PI3K/mTOR pathway is commonly deregulated in cancer. mTOR inhibitors are registered for the treatment of several solid tumors and novel inhibitors are explored clinically. Notably, this pathway also plays an important role in immunoregulation. While mTOR inhibitors block cell cycle progression of conventional T cells (Tconv), they also result in the expansion of CD4+ CD25hiFOXP3+ regulatory T cells (Tregs), and this likely limits their clinical antitumor efficacy. Here, we compared the effects of dual mTOR/PI3K inhibition (using BEZ235) to single PI3K (using BKM120) or mTOR inhibition (using rapamycin and everolimus) on Treg expansion and functionality. Whereas rapamycin, everolimus and BEZ235 effected a relative expansion benefit for Tregs and increased their overall suppressive activity, BKM120 allowed for similar expansion rates of Tregs and Tconv without altering their overall suppressive activity. Therefore, PI3K inhibition alone might offer antitumor efficacy without the detrimental selective expansion of Tregs associated with mTOR inhibition.

Abbreviations

iTregs
in vitro-induced Tregs
LAP
Latency Associated Peptide
PD-1
programmed death-1
pNET
pancreatic neuroendocrine tumor
PTEN
phosphatase and tensin homolog deleted on chromosome 10
pTregs
peripherally derived Tregs
Tconv
conventional T cells
Tregs
CD4+ CD25hiFOXP3+ regulatory T cells
tTregs
thymus derived Tregs

Keywords

Rapamycin
Treg
PI3K
mTOR

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