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EBioMedicine. 2016 Jan 16;4:50-61. doi: 10.1016/j.ebiom.2016.01.019. eCollection 2016 Feb.

Modulation of mTOR Signalling Triggers the Formation of Stem Cell-like Memory T Cells.

Author information

1
Translational Tumor Immunology Group, Ludwig Cancer Research (LICR), University of Lausanne (UNIL), 1066 Epalinges, Vaud, Switzerland.
2
Lymphocyte Function Group, LICR, UNIL, Switzerland.
3
Department of Physiology, UNIL, 1015 Lausanne, Vaud, Switzerland.
4
Bioinformatics Core Facility, Swiss Institute of Bioinformatics, UNIL, Switzerland.
5
Bioinformatics Core Facility, Swiss Institute of Bioinformatics, UNIL, Switzerland; LICR, UNIL, Switzerland; Department of Oncology, Lausanne University Hospital (CHUV), 1011 Lausanne, Vaud, Switzerland.
6
Department of Visceral Surgery, CHUV, Switzerland.
7
Translational Tumor Immunology Group, Ludwig Cancer Research (LICR), University of Lausanne (UNIL), 1066 Epalinges, Vaud, Switzerland; Department of Oncology, Lausanne University Hospital (CHUV), 1011 Lausanne, Vaud, Switzerland.

Abstract

Robust, long-lasting immune responses are elicited by memory T cells that possess properties of stem cells, enabling them to persist long-term and to permanently replenish the effector pools. Thus, stem cell-like memory T (TSCM) cells are of key therapeutic value and efforts are underway to characterize TSCM cells and to identify means for their targeted induction. Here, we show that inhibition of mechanistic/mammalian Target of Rapamycin (mTOR) complex 1 (mTORC1) by rapamycin or the Wnt-β-catenin signalling activator TWS119 in activated human naive T cells leads to the induction of TSCM cells. We show that these compounds switch T cell metabolism to fatty acid oxidation as favoured metabolic programme for TSCM cell generation. Of note, pharmacologically induced TSCM cells possess superior functional features as a long-term repopulation capacity after adoptive transfer. Furthermore, we provide insights into the transcriptome of TSCM cells. Our data identify a mechanism of pharmacological mTORC1 inhibitors, allowing us to confer stemness to human naive T cells which may be significantly relevant for the design of innovative T cell-based cancer immunotherapies.

KEYWORDS:

Adoptive cell transfer therapy; Human T cells; Rapamycin; T cell differentiation

Comment in

PMID:
26981571
PMCID:
PMC4776068
DOI:
10.1016/j.ebiom.2016.01.019
[Indexed for MEDLINE]
Free PMC Article

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