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 Edward Janik, Samir N. Khleif

Research output: Contribution to journalArticle

15 Citations (Scopus)

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 na�ve 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 na�ve 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 (US)
JournalOncoImmunology
Volume4
Issue number5
DOIs
StatePublished - Jan 1 2015

Fingerprint

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 and Allergy
  • Immunology
  • Oncology

Cite this

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

In: OncoImmunology, Vol. 4, No. 5, 01.01.2015.

Research output: Contribution to journalArticle

Eid, Rasha Abu ; Friedman, Kevin M. ; Mkrtichyan, Mikayel ; Walens, Andrea ; King, William ; Janik, John Edward ; 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.
@article{a8d9f80f68514fe4b0efa2374b953f36,
title = "Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8+ T-cell proliferation and survival",
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 na{\"i}¿½ve 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 na{\"i}¿½ve 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.",
keywords = "Akt, Central memory, Effector memory, Proliferation, T cells",
author = "Eid, {Rasha Abu} and Friedman, {Kevin M.} and Mikayel Mkrtichyan and Andrea Walens and William King and Janik, {John Edward} and Khleif, {Samir N.}",
year = "2015",
month = "1",
day = "1",
doi = "10.1080/2162402X.2015.1005448",
language = "English (US)",
volume = "4",
journal = "OncoImmunology",
issn = "2162-4011",
publisher = "Landes Bioscience",
number = "5",

}

TY - JOUR

T1 - Akt1 and -2 inhibition diminishes terminal differentiation and enhances central memory CD8+ T-cell proliferation and survival

AU - Eid, Rasha Abu

AU - Friedman, Kevin M.

AU - Mkrtichyan, Mikayel

AU - Walens, Andrea

AU - King, William

AU - Janik, John Edward

AU - Khleif, Samir N.

PY - 2015/1/1

Y1 - 2015/1/1

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 na�ve 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 na�ve 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 na�ve 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 na�ve 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.

KW - Akt

KW - Central memory

KW - Effector memory

KW - Proliferation

KW - T cells

UR - http://www.scopus.com/inward/record.url?scp=84944463344&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84944463344&partnerID=8YFLogxK

U2 - 10.1080/2162402X.2015.1005448

DO - 10.1080/2162402X.2015.1005448

M3 - Article

AN - SCOPUS:84944463344

VL - 4

JO - OncoImmunology

JF - OncoImmunology

SN - 2162-4011

IS - 5

ER -