Colliver, Emma Charlotte; (2024) Deciphering the non-small cell lung cancer tumour microenvironment using imaging mass cytometry. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The tumour microenvironment (TME) is a clinically actionable target in tumour biology. Deciphering the microenvironmental context of cancer genome evolution will shed light on the selective pressures which shape the expansion of immune-evading subclones. Imaging mass cytometry (IMC) is a multiplexed imaging technique which permits interrogation of multiple TME cell phenotypes simultaneously while retaining information about tissue architecture. Since the relative positioning of cell subtypes dictates their function, imaging can reveal novel immune evasion mechanisms, therapeutic targets and biomarkers of treatment response associated with cellular organisation. In this thesis, paired IMC, whole exome sequencing and RNA-sequencing data were used to interrogate the lung cancer TME and associations with tumour genetics in 81 patients with early-stage treatment-naïve non-small cell lung cancer (n=198 regions, 2.3million cells) from the TRACERx study. A novel hybrid deep learning-classical cell segmentation method was developed to extract single-cell information from IMC images and describe microenvironmental composition in tumour and normal lung tissue, while tools Refphase and CONIPHER were developed to improve resolution of subclonal structure. Integrating IMC-derived single-cell data with paired genetics, plasma cells were found to be enriched in high TMB tumour regions. Tregs and dysfunctional T cells were enriched in KRASmut adenocarcinomas, and neutrophils in PIK3CAmut squamous cell carcinomas (LUSC). TME associations with neoantigen burden, calculated considering lost HLA genes, differed between histologies. Cancer antigen presentation dysfunction was most frequent in TMEs characterised by TIL and macrophage infiltration into tumour nests whereas immune low TMEs were characterised by increased spatial inter-positioning of ɑSMA fibroblasts between CD8 T cells and tumour cells. Finally, neutrophil-rich TMEs were associated with expanded tumour subclones and in LUSC reduced vasculature and tumour MCT4 expression. Together, this is the first lung cancer study to integrate highly multiplexed imaging and genetics data, providing new insights into the microenvironmental context of cancer evolution.

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