Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8(+) T-cell proliferation and survival

Rasha Abu Eid, Kevin M Friedman, Mikayel Mkrtichyan, Andrea Walens, William King, John Janik, Samir N Khleif

Research output: Contribution to journalArticle

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Abstract

The CD8 (+) T-cell response comprises terminally differentiated effector cells and antigen-experienced memory T cells. The latter encompass central (TCM) and effector (TEM) memory cells. TCM cells are superior in their protection against viral and bacterial challenges and mediation of antitumor immunity due to their higher proliferative ability upon antigen re-encounter. Defining a mechanism to enhance TCM cells and delay terminal differentiation of CD8 (+) T cells is crucial for cancer immune therapy, as it can promote a better tumor immune response. The differentiation of CD8 (+) memory T cells is thought to be coordinated by the phosphoinositide 3-kinase (PI3K)/Akt pathway. We, therefore, investigated the role of Akt isoforms in the differentiation and proliferation of memory CD8 (+) T cells. We found that Akt1 and Akt2, but not Akt3, drive the terminal differentiation of CD8 (+) T cells, and their inhibition enhances the therapeutically superior TCM phenotype. Furthermore, the inhibition of Akt1 and Akt2, but not Akt 3, delays CD8 (+) T-cell exhaustion and preserves naïve and TCM CD8 (+) T cells, thus enhancing their proliferative ability and survival and prolonging their cytokine and Granzyme B production ability. Here, we define a mechanism in which proliferative potential, function, and survival of CD8 (+) T cells are enhanced by maintaining a reservoir of TCM and naïve cells using only Akt1 and Akt2 inhibition. Therefore, our findings strongly suggest the utility of using Akt1 and Akt2 inhibitors to modulate CD8 (+) T cells, both for adoptive cell transfer and vaccine-based cancer immune therapies.

Original languageEnglish
Pages (from-to)e1005448-1-11
Number of pages11
JournalOncoimmunology
Volume4
Issue number5
Early online date3 Feb 2015
DOIs
Publication statusPublished - May 2015

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Cell Survival
Cell Proliferation
T-Lymphocytes
Antigens
Granzymes
Cancer Vaccines
1-Phosphatidylinositol 4-Kinase
Adoptive Transfer
Immunity
Neoplasms
Protein Isoforms
Cytokines
Phenotype
Therapeutics

Keywords

  • Akt
  • central memory
  • effector memory
  • proliferation
  • T cells

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8(+) T-cell proliferation and survival. / Abu Eid, Rasha; Friedman, Kevin M; Mkrtichyan, Mikayel; Walens, Andrea; King, William; Janik, John; Khleif, Samir N.

In: Oncoimmunology, Vol. 4, No. 5, 05.2015, p. e1005448-1-11.

Research output: Contribution to journalArticle

Abu Eid, Rasha ; Friedman, Kevin M ; Mkrtichyan, Mikayel ; Walens, Andrea ; King, William ; Janik, John ; Khleif, Samir N. / Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8(+) T-cell proliferation and survival. In: Oncoimmunology. 2015 ; Vol. 4, No. 5. pp. e1005448-1-11.
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AU - Abu Eid, Rasha

AU - Friedman, Kevin M

AU - Mkrtichyan, Mikayel

AU - Walens, Andrea

AU - King, William

AU - Janik, John

AU - Khleif, Samir N

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N2 - The CD8 (+) T-cell response comprises terminally differentiated effector cells and antigen-experienced memory T cells. The latter encompass central (TCM) and effector (TEM) memory cells. TCM cells are superior in their protection against viral and bacterial challenges and mediation of antitumor immunity due to their higher proliferative ability upon antigen re-encounter. Defining a mechanism to enhance TCM cells and delay terminal differentiation of CD8 (+) T cells is crucial for cancer immune therapy, as it can promote a better tumor immune response. The differentiation of CD8 (+) memory T cells is thought to be coordinated by the phosphoinositide 3-kinase (PI3K)/Akt pathway. We, therefore, investigated the role of Akt isoforms in the differentiation and proliferation of memory CD8 (+) T cells. We found that Akt1 and Akt2, but not Akt3, drive the terminal differentiation of CD8 (+) T cells, and their inhibition enhances the therapeutically superior TCM phenotype. Furthermore, the inhibition of Akt1 and Akt2, but not Akt 3, delays CD8 (+) T-cell exhaustion and preserves naïve and TCM CD8 (+) T cells, thus enhancing their proliferative ability and survival and prolonging their cytokine and Granzyme B production ability. Here, we define a mechanism in which proliferative potential, function, and survival of CD8 (+) T cells are enhanced by maintaining a reservoir of TCM and naïve cells using only Akt1 and Akt2 inhibition. Therefore, our findings strongly suggest the utility of using Akt1 and Akt2 inhibitors to modulate CD8 (+) T cells, both for adoptive cell transfer and vaccine-based cancer immune therapies.

AB - The CD8 (+) T-cell response comprises terminally differentiated effector cells and antigen-experienced memory T cells. The latter encompass central (TCM) and effector (TEM) memory cells. TCM cells are superior in their protection against viral and bacterial challenges and mediation of antitumor immunity due to their higher proliferative ability upon antigen re-encounter. Defining a mechanism to enhance TCM cells and delay terminal differentiation of CD8 (+) T cells is crucial for cancer immune therapy, as it can promote a better tumor immune response. The differentiation of CD8 (+) memory T cells is thought to be coordinated by the phosphoinositide 3-kinase (PI3K)/Akt pathway. We, therefore, investigated the role of Akt isoforms in the differentiation and proliferation of memory CD8 (+) T cells. We found that Akt1 and Akt2, but not Akt3, drive the terminal differentiation of CD8 (+) T cells, and their inhibition enhances the therapeutically superior TCM phenotype. Furthermore, the inhibition of Akt1 and Akt2, but not Akt 3, delays CD8 (+) T-cell exhaustion and preserves naïve and TCM CD8 (+) T cells, thus enhancing their proliferative ability and survival and prolonging their cytokine and Granzyme B production ability. Here, we define a mechanism in which proliferative potential, function, and survival of CD8 (+) T cells are enhanced by maintaining a reservoir of TCM and naïve cells using only Akt1 and Akt2 inhibition. Therefore, our findings strongly suggest the utility of using Akt1 and Akt2 inhibitors to modulate CD8 (+) T cells, both for adoptive cell transfer and vaccine-based cancer immune therapies.

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KW - effector memory

KW - proliferation

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