title: Modulation of mTOR Signalling Triggers the Formation of Stem Cell-like Memory T Cells.
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.
authors.affiliation: Translational Tumor Immunology Group, Ludwig Cancer Research (LICR), University of Lausanne (UNIL), 1066 Epalinges, Vaud, Switzerland.
authors.forename: Godehard
authors.initials: G
authors.lastname: Scholz
authors.affiliation: Translational Tumor Immunology Group, Ludwig Cancer Research (LICR), University of Lausanne (UNIL), 1066 Epalinges, Vaud, Switzerland.
authors.forename: Camilla
authors.initials: C
authors.lastname: Jandus
authors.affiliation: Translational Tumor Immunology Group, Ludwig Cancer Research (LICR), University of Lausanne (UNIL), 1066 Epalinges, Vaud, Switzerland.
authors.forename: Lianjun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Lymphocyte Function Group, LICR, UNIL, Switzerland.
authors.forename: Camille
authors.initials: C
authors.lastname: Grandclément
authors.affiliation: Department of Physiology, UNIL, 1015 Lausanne, Vaud, Switzerland.
authors.forename: Isabel C
authors.initials: IC
authors.lastname: Lopez-Mejia
authors.affiliation: Bioinformatics Core Facility, Swiss Institute of Bioinformatics, UNIL, Switzerland.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Soneson
authors.affiliation: Bioinformatics Core Facility, Swiss Institute of Bioinformatics, UNIL, Switzerland; LICR, UNIL, Switzerland; Department of Oncology, Lausanne University Hospital (CHUV), 1011 Lausanne, Vaud, Switzerland.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: Department of Physiology, UNIL, 1015 Lausanne, Vaud, Switzerland.
authors.forename: Lluis
authors.initials: L
authors.lastname: Fajas
authors.affiliation: Lymphocyte Function Group, LICR, UNIL, Switzerland.
authors.forename: Werner
authors.initials: W
authors.lastname: Held
authors.affiliation: Department of Visceral Surgery, CHUV, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Dormond
authors.affiliation: 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.
authors.forename: Pedro
authors.initials: P
authors.lastname: Romero
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D038041:Lymphopoiesis; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054504:Precursor Cells, T-Lymphoid / Q000166:cytology* / Q000276:immunology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; D011743:Pyrimidines; D011758:Pyrroles; C547688:TWS 119; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
keywords: Adoptive cell transfer therapy; Human T cells; Rapamycin; T cell differentiation