Alvares, B; (2015) Engineering T cells to overcome the hostile tumour microenvironment. Doctoral thesis , UCL (University College London).

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Abstract

Adoptive immunotherapy with autologous T lymphocytes transduced with anti-tumour antigen-specific T cell receptors (TCRs) has emerged as a promising anti-cancer therapy. In vitro studies have suggested that T cell function may be limited by tumour associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs). This study aims to determine the influence of TAMs and MDSCs on the antigen-specific function of TCR-transduced T cells in vitro and in vivo. Two murine tumour models, the EL4 lymphoma and ID8 ovarian carcinoma were modified to ensure that CD8+ T cells transduced with the F5-TCR recognised tumour cells expressing a model target antigen, Influenza A Nucleoprotein (NP) in the presence of tumour-infiltrating TAMs and MDSCs. It was demonstrated that Gr-1+ MDSCs isolated from tumour-bearing mice failed to suppress F5-TCR CD8+ T cells in vitro. Moreover, in vivo depletion of Gr-1+ MDSCs following the administration of an anti-Gr-1 antibody did not affect the anti-tumour function of adoptively transferred F5-TCR CD8+ T cells. Interestingly, bone marrow-derived CD115+ monocytes potently suppressed T cell proliferation in vitro, although these cells failed to impair the anti-tumour function of F5-TCR CD8+ T cells in vivo when adoptively transferred to EL4-NP tumour-bearing mice. This suggested that Gr-1+ MDSCs and/or CD115+ monocytes may not significantly impair the anti-tumour efficacy of CD8+ T cells expressing high avidity TCR in the tumour models examined. Further experiments are warranted to explore their impact on tumour antigen-specific T cells at lower frequencies and/or with lower avidity.

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