Modulating mTOR activity to control T cell function

This presentation was given by Hans Stauss from the Institute of Immunity & Transplantation at University College London and the Cell Medica Scientific Advisory Board. It was presented at the ISN’s Forefronts Symposium 2015 taking place in Shenzhen, China, on October 22-25, 2015 for which the theme was ‘Immunomodulation of Cardio-Renal Function’ during Session 3: Immunology and Metabolism – Immuno-Metabolism, an Emerging Frontier.

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Presentation Abstract: 

A key challenge in the field of T cell immunotherapy for cancer and infection is creating a suitable platform for promoting differentiation of effector cells while at the same time enabling self-renewal needed for long-term memory.  Although transfer of less differentiated memory T cells increases efficacy through greater expansion and persistence in vivo, the capacity of such cells to sustain effector functions within immunosuppressive tumor microenvironments may still be limiting.  We have therefore directly compared the impact of effector versus memory differentiation of therapeutic T cells in tumor-bearing mice by introducing molecular switches that regulate cell fate decisions via mTOR.  

Ectopic expression of RAS homologue enriched in brain (RHEB) increased mTOR complex 1 (mTORC1) signaling, promoted a switch to aerobic glycolysis and increased expansion of effector T cells.  By rapidly infiltrating tumors, RHEB-transduced T cells significantly reduced the emergence of immunoedited escape variants.  In contrast, expression of proline-rich Akt substrate of 40kDa (PRAS40) inhibited mTORC1, promoted quiescence and blocked tumor infiltration. Fate mapping studies following transient expression of PRAS40 demonstrated that mTORC1low T cells made no contribution to initial tumor control but instead survived to become memory cells proficient in generating recall immunity. Our data support the design of translational strategies for generating heterogeneous T cell immunity against cancer, with the appropriate balance between promoting effector differentiation and self-renewal.  Unlike pharmacological inhibitors, the genetic approach described here allows for up-regulation as well as inhibition of the mTORC1 pathway, and is highly selective for the therapeutic T cells without affecting systemic mTORC1 functions.