Whiteman, Zoe Emma; (2023) Therapeutic potential of PI3K signalling in lung squamous cell carcinoma. Doctoral thesis (Ph.D), UCL (University College London).

Text Zoe_E_Whiteman_Thesis_26012023.pdf - Accepted Version Access restricted to UCL open access staff until 1 May 2025. Download (9MB)

Abstract

Lung cancer is the leading cause of cancer-related death worldwide. Lung squamous cell carcinoma (LUSC), a lung cancer subtype, develops through multiple pre-invasive disease grades that progress to invasive LUSC. This presents opportunities for interventional therapies to halt LUSC development at pre-invasive stages, to improve patient prognosis. Here, I investigated the therapeutic potential of targeting phosphoinositide 3-kinase (PI3K) signalling during LUSC development. I used both in vitro and in vivo approaches to examine disease-intrinsic and microenvironment features that may influence disease fate. I optimised strategies to develop a human in vitro model to study the common genetic changes associated with dysregulated PI3Kα signalling in LUSC. Such a model will enable mechanistic insight into the prevalence of these genomic changes. In the N-nitroso-tris-chloroethylurea (NTCU)-induced LUSC murine pre-clinical model, which histologically recapitulates both pre-invasive and invasive LUSC, I evaluated changes in PI3Kα signalling and T-lymphocyte populations, in situ. Using this model, I also assessed PI3Kα and PI3Kδ inhibitors as interventional LUSC therapies. I demonstrate that PI3Kα signalling may have a heterogeneous role in NTCU-induced disease, and that the lung T-cell immune composition undergoes dynamic changes during LUSC development. CD4+FOXP3+ regulatory T-cells accumulate in proximity to the bronchial tree, including areas of pre-invasive and invasive disease, likely promoting an immunosuppressive environment that facilitates disease progression. 5 Modulating PI3Kα signalling, by BYL719 treatment, had no effect on NTCU-induced disease development. However, the PI3Kδ inhibitor PI-3065, a small molecule that impairs regulatory T-cell maintenance and functionality, reduced NTCU-induced tumour incidence and size. This was associated with fewer regulatory T-cells in proximity to disease, and an increased cytotoxic tumour immune microenvironment. This study supports recent work describing the importance of the immune microenvironment in determining pre-invasive disease fate. My work also highlights regulatory T-cell-targeted immunomodulatory treatments, such as PI3Kδ inhibition, as important interventional lung cancer therapeutic candidates.

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