Selective Inhibition of Regulatory T Cells by Targeting the PI3K–Akt Pathway

Rasha Abu-Eid, Raed N Samara, Laurent Ozbun, Maher Y Abdalla, Jay A Berzofsky, Kevin M Friedman, Mikayel Mkrtichyan, Samir N Khleif

Research output: Contribution to journalArticle

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Abstract

Despite the strides that immunotherapy has made in mediating tumor regression, the clinical effects are often transient, and therefore more durable responses are still needed. The temporary nature of the therapy-induced immune response can be attributed to tumor immune evasion mechanisms, mainly the effect of suppressive immune cells and, in particular, regulatory T cells (Treg). Although the depletion of Tregs has been shown to be effective in enhancing immune responses, selective depletion of these suppressive cells without affecting other immune cells has not been very successful, and new agents are sought. We found that PI3K-Akt pathway inhibitors selectively inhibit Tregs with minimal effect on conventional T cells (Tconv). Our results clearly show selective in vitro inhibition of activation (as represented by a decrease in downstream signaling) and proliferation of Tregs in comparison with Tconvs when treated with different Akt and PI3K inhibitors. This effect has been observed in both human and murine CD4 T cells. In vivo treatment with these inhibitors resulted in a significant and selective reduction in Tregs in both naïve and tumor-bearing mice. Furthermore, these PI3K-Akt inhibitors led to a significant therapeutic antitumor effect, which was shown to be Treg dependent. Here, we report the use of PI3K-Akt pathway inhibitors as potent agents for the selective depletion of suppressive Tregs. We show that these inhibitors are able to enhance the antitumor immune response and are therefore promising clinical reagents for Treg depletion.

Original languageEnglish
Pages (from-to)1080-1089
Number of pages10
JournalCancer immunology research
Volume2
Issue number11
Early online date30 Jul 2014
DOIs
Publication statusPublished - Nov 2014

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Regulatory T-Lymphocytes
Phosphatidylinositol 3-Kinases
Tumor Escape
T-Lymphocytes
Therapeutic Uses
Immunotherapy
Neoplasms
Therapeutics

Keywords

  • Animals
  • Female
  • Flow Cytometry
  • Humans
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Signal Transduction
  • T-Lymphocytes, Regulatory
  • Journal Article

Cite this

Abu-Eid, R., Samara, R. N., Ozbun, L., Abdalla, M. Y., Berzofsky, J. A., Friedman, K. M., ... Khleif, S. N. (2014). Selective Inhibition of Regulatory T Cells by Targeting the PI3K–Akt Pathway. Cancer immunology research, 2(11), 1080-1089. https://doi.org/10.1158/2326-6066.CIR-14-0095

Selective Inhibition of Regulatory T Cells by Targeting the PI3K–Akt Pathway. / Abu-Eid, Rasha; Samara, Raed N; Ozbun, Laurent; Abdalla, Maher Y; Berzofsky, Jay A; Friedman, Kevin M; Mkrtichyan, Mikayel; Khleif, Samir N.

In: Cancer immunology research, Vol. 2, No. 11, 11.2014, p. 1080-1089.

Research output: Contribution to journalArticle

Abu-Eid, R, Samara, RN, Ozbun, L, Abdalla, MY, Berzofsky, JA, Friedman, KM, Mkrtichyan, M & Khleif, SN 2014, 'Selective Inhibition of Regulatory T Cells by Targeting the PI3K–Akt Pathway', Cancer immunology research, vol. 2, no. 11, pp. 1080-1089. https://doi.org/10.1158/2326-6066.CIR-14-0095
Abu-Eid, Rasha ; Samara, Raed N ; Ozbun, Laurent ; Abdalla, Maher Y ; Berzofsky, Jay A ; Friedman, Kevin M ; Mkrtichyan, Mikayel ; Khleif, Samir N. / Selective Inhibition of Regulatory T Cells by Targeting the PI3K–Akt Pathway. In: Cancer immunology research. 2014 ; Vol. 2, No. 11. pp. 1080-1089.
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AU - Friedman, Kevin M

AU - Mkrtichyan, Mikayel

AU - Khleif, Samir N

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N2 - Despite the strides that immunotherapy has made in mediating tumor regression, the clinical effects are often transient, and therefore more durable responses are still needed. The temporary nature of the therapy-induced immune response can be attributed to tumor immune evasion mechanisms, mainly the effect of suppressive immune cells and, in particular, regulatory T cells (Treg). Although the depletion of Tregs has been shown to be effective in enhancing immune responses, selective depletion of these suppressive cells without affecting other immune cells has not been very successful, and new agents are sought. We found that PI3K-Akt pathway inhibitors selectively inhibit Tregs with minimal effect on conventional T cells (Tconv). Our results clearly show selective in vitro inhibition of activation (as represented by a decrease in downstream signaling) and proliferation of Tregs in comparison with Tconvs when treated with different Akt and PI3K inhibitors. This effect has been observed in both human and murine CD4 T cells. In vivo treatment with these inhibitors resulted in a significant and selective reduction in Tregs in both naïve and tumor-bearing mice. Furthermore, these PI3K-Akt inhibitors led to a significant therapeutic antitumor effect, which was shown to be Treg dependent. Here, we report the use of PI3K-Akt pathway inhibitors as potent agents for the selective depletion of suppressive Tregs. We show that these inhibitors are able to enhance the antitumor immune response and are therefore promising clinical reagents for Treg depletion.

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KW - Proto-Oncogene Proteins c-akt

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JO - Cancer immunology research

JF - Cancer immunology research

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