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

• Immunostimulatory effect of rapamycin on induction of TSCM cells
• Previously unknown mTORC1 inhibiting drug effect of the Wnt activator TWS119
• Insights into the metabolic regulation of human CD4 + TSCM cells and into their transcriptomeStem cell-like memory T (TSCM) cells represent the newly identified memory T cell subset, which harbours key therapeutic value by its self-renewal capacity and ability to generate memory and effector T cells. However, the signalling pathways controlling TSCM cell formation remain incompletely understood. Here, we present the induction of CD4 + TSCM cells from highly purified naïve cells by pharmacological inhibition of mTORC1 by either rapamycin or TWS119. We carried out comprehensive transcriptome and metabolic analyses of induced and naturally occurring TSCM cells. Targeted induction of TSCM cells by pharmacological means is highly relevant for the design of novel immunotherapeutic approaches.

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.