Skip to content

Advertisement

  • Poster presentation
  • Open Access

AKT inhibition mitigates terminal differentiation and preserves central memory phenotype of CD8 T cells

  • 1,
  • 2,
  • 1 and
  • 1
Journal for ImmunoTherapy of Cancer20142 (Suppl 3) :P93

https://doi.org/10.1186/2051-1426-2-S3-P93

  • Published:

Keywords

  • Immune Therapy
  • Bacterial Challenge
  • Expansion Ability
  • High Proliferative Ability
  • Central Memory Phenotype

Introduction

CD8 T cell response comprises effector and memory T cells. Effector CD8 T cells become terminally differentiated and are eliminated by apoptosis. Memory CD8 T cells encompass central (TCM) and effector memory T cells (TEM). TCM display a higher proliferative ability, express a higher level of CD62L and are superior in their protection against viral and bacterial challenges and mediation of anti-tumor immunity when compared to TEM. The differentiation of CD8 T cell is thought to be coordinated by the PI3K/Akt pathway.

Methods

The effect of in vitro Akt inhibition using the pan Akt inhibitors MK-2206 and AZD5363 on the differentiation and proliferation of CD8 T cells was examined. Cell proliferation, expansion, cytokine production and phenotype were assessed in antigen specific CD8 T cells.

Results

We found that the inhibition of Akt leads to a significant enhancement of the proliferative potential of CD8 T cells, and to prolongation of their survival upon TCR re-stimulation. Furthermore, we found that Akt inhibition leads to increase in IL-2 secretion, a marker of cells with high proliferative ability. We further identified that Akt inhibition preserved the TCM phenotype by conserving a higher percentage of (CD44HI CD62LHI) expressing T cells. These cells also displayed a higher level of CD127 and a lower level of the exhaustion marker KLRG-1 reflecting their increased expansion ability and longevity due to Akt inhibition. Additionally, we found that Akt inhibition also resulted in the preservation of a significantly higher percentage of naïve CD8 T cells (CD44LO CD62LHI) when compared to the non-treated cells.

Conclusion

Here, we show that Akt inhibition preserves the central memory phenotype of CD8 T cells thus enhancing their proliferation, survival and cytokine production. Furthermore, Akt inhibition results in the conservation of a reservoir of naïve CD8 T cells. Both naïve and TCM CD8 T cells are superior mediators of anti-tumor immunity when compared to effector or TEM cells. These findings strongly suggest the utility of using Akt inhibitors to modulate the immune response as part of cancer immune therapy.

Authors’ Affiliations

(1)
Georgia Regents University Cancer Center, Augusta, GA, USA
(2)
bluebird Bio, Cambridge, MA, USA

Copyright

Advertisement