Furness, Andrew J.S.; (2018) T cell reactivity and regulation in human cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Modulation of co-inhibitory and co-stimulatory immune checkpoint molecules with antibody-based therapies has emerged as a promising anti-cancer strategy, however response rates to such agents are modest. The discrepancy in activity observed between mouse models and human cancers is rarely acknowledged, but deciphering this might provide valuable insights into underlying mechanisms of response and resistance. Through parallel analysis of mouse models and human cancers, this study demonstrates the importance of the local microenvironment in determining the activity of immune modulatory antibodies (mAb), providing novel insights into the mechanism of anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4, CD152) and anti-interleukin-2 receptor alpha chain (IL-2Rα, CD25) antibodies. A limitation of such approaches is the requirement for a pre-existing T cell infiltrate. In human tumours, paucity of immune infiltrate is well recognised, highlighting the need to identify relevant drivers of T cell infiltration. Complementary analysis of genomic and immunological landscapes in human tumours demonstrates that beyond total neoantigen burden, clonal architecture influences anti-tumour immunity, with prognostic implication and predictive value in the context of immune checkpoint modulation. Targeting clonal neoantigens, present on every tumour cell, might hold promise in overcoming the significant therapeutic challenge posed by tumour evolution and consequent intra-tumour heterogeneity.

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