Zech, MH; (2014) Genetic Control of MTOR to Improve Adoptive T Cell Therapy of Tumours. Doctoral thesis , UCL (University College London).

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Abstract

Adoptive T cell therapy to treat cancer in combination with re-directing specificity through T cell receptor (TCR) gene transfer, represents an effective therapeutic option. However, reduced effector responses due to the immunosuppressive tumour microenvironment and insufficient long-term engraftment of transferred cells represent two potential limitations. Tumours often employ mechanisms to inhibit T cell responses including secretion of TGFβ and depleting the tumour microenvironment of amino acids. The main aim of this PhD project was to develop a strategy to enhance T cell function for tumour therapy. The mammalian target of rapamycin (mTOR) pathway regulates CD8 T cell differentiation such that high mTOR activation leads to enhanced effector whilst low mTOR activation leads to increased T cell memory formation. Two retrovirus constructs have been designed whereby one expresses the positive mTOR regulator Rheb and the other expresses the negative mTOR regulator Pras40. Rheb transduction into CD8 T cells resulted in enhanced activation of mTOR, increased effector functions and partial resistance to TGFβ and low arginine concentrations. Pras40 overexpression led to a decrease in the activation of mTOR and reduced effector functions. Rheb transduced CD8 T cells expanded efficiently upon antigen encounter in vivo, followed by pronounced T cell contraction. Pras40 transduced T cells were unable to expand in vivo, but persisted at low numbers and acquired a central memory phenotype. Tumour bearing mice treated with TCR re-directed CD8 T cells transduced with Rheb showed improved tumour protection. Pras40 overexpression resulted in the loss of the protective function of TCR re-directed T cells. Together, the data show that gene transfer can be used to regulate mTOR activity in T cells. Enhancing mTOR activity led to improved tumour control despite reducing memory formation. Permanent mTOR inhibition, on the other hand, preserved some memory characteristcs of T cells but deteriorated their tumour protective functions.

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