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  • Open Access

Inhibition of mTORC2/Akt signaling to enhance the therapeutic potential of CD8 T cells

  • Lianjun Zhang1,
  • Benjamin Tschumi1,
  • Susanne Oberle2,
  • Markus Ruegg3,
  • Michael Hall3,
  • Dietmar Zehn2,
  • Jean-Pierre Mach4,
  • Alena Donda1 and
  • Pedro Romero1
Journal for ImmunoTherapy of Cancer20153(Suppl 2):P330

https://doi.org/10.1186/2051-1426-3-S2-P330

Published: 4 November 2015

Keywords

Protective Immune ResponseMouse MelanomaIntrinsic SignalingMetabolic ReprogramAdoptive Cell Transfer

CD8 T cells mediate protective immune responses against infections and cancer. Upon infection, antigen-specific naïve CD8 T cells are activated and differentiate into short-lived effector (SLEC) and memory precursor cells (MPEC). The T cell intrinsic signaling pathways underlying this differentiation remain largely unresolved. Here we show that Rictor, the core component of mammalian target of rapamycin complex 2 (mTORC2), regulates SLEC and MPEC commitment. Rictor deficient T cells form enhanced memory without dampening effector function, have increased IL-2 secretion capacity and mediate more potent recall responses. Mechanistically, enhanced memory formation in the absence of functional mTORC2 was associated with transcriptional and metabolic reprogramming by Eomes and Tcf-1 upregulation, repression of T-bet and nuclear stabilization of Foxo1. Elimination of Foxo1 reversed the increased MPECs differentiation and IL-2 production in Rictor KO mice. Effective T cell therapy against cancer depends highly on the generation of long-term persistent memory CD8 T cells. Our preliminary data show that Rictor deficient CD8 T cells show superior tumor protection effects in mouse melanoma model. Together, our study identifies mTORC2 as a central regulator of CD8 T cell differentiation and inhibition of mTORC2 or Akt might represent an effective strategy for both adoptive cell transfer and vaccine-based cancer therapies.

Authors’ Affiliations

(1)
Ludwig Cancer Research of University of Lausanne, Switzerland, Switzerland
(2)
Swiss Vaccine Research Institute,, Switzerland, Switzerland
(3)
Biozentrum, University of Basel, Basel, Switzerland, Switzerland
(4)
Department of Biochemistry, University of Lausanne, Epalinges, Switzerland, Switzerland

Copyright

© Zhang et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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