Fitzsimons, Evelyn Mary; (2025) Hallmarks of the anti-tumour immune response for early detection of lung cancer; insights from the NIMBLE study. Doctoral thesis (Ph.D), UCL (University College London).

Text Evelyn Mary Fitzsimons PhD Thesis.pdf - Submitted Version Access restricted to UCL open access staff until 1 December 2026. Download (39MB)

Abstract

Up to 50% of cancer patients are diagnosed at a late stage, leading to intensive treatments and a preventable loss of life. Current approaches, such as circulating tumour DNA (ctDNA), have limited sensitivity and specificity for early-stage malignancy, underscoring an urgent need for novel early detection strategies. Immune perturbations arise at the earliest stages of tumorigenesis, offering the potential for an intrinsically sensitive and specific system for early cancer detection. Yet key components of this response remain poorly characterised. This thesis addresses two major gaps. First, the role of intratumoral B cells in cancer immunity has received little attention, despite growing evidence for their functional diversity and clinical relevance. I created a pan-cancer scRNAseq atlas of B cell subsets in the tumour microenvironment, offering broader and deeper annotation than previous atlases limited to single cancer types or narrower immune populations. Second, I investigate whether immune features in peripheral blood can support development of an early lung cancer diagnostic assay. This work draws on the Nodule Immunophenotyping Biomarker for Lung Cancer Early Diagnosis (NIMBLE) study, a prospective cohort of 500 patients with indeterminate pulmonary nodules and longitudinal follow-up. This represents the first immune-focused study of early lung cancer in a clinically relevant population with deeply annotated biospecimens. High-dimensional spectral flow cytometry with panels comprising 72 markers in total revealed substantial heterogeneity across circulating lymphocytes, including diverse CD8⁺, CD4⁺, and B cell subsets. Both unsupervised clustering and manual gating identified cancer-associated changes. Malignant nodules were associated with increased mucosal-associated invariant T (MAIT) cells with phenotypic remodelling, as well as alterations in CD8⁺ T cells (increased CD38), CD4⁺ T cells (increased CD103 on regulatory and non-regulatory subsets), and B cells (increased TIGIT, CCR7, and PD-1 with reduced T-bet). Complementary cytokine bead array profiling of matched serum samples demonstrated a systemic pro-inflammatory and cytotoxic signature, with elevated perforin, granulysin, sFas, CCL3, CXCL9, CXCL10, and IL-6. No cancer-specific antibody reactivities were detected. Together, these findings define four axes of immune remodelling in early lung cancer: systemic cytotoxic priming, MAIT cell remodelling, regulatory imprinting of CD4⁺ T cells, and checkpoint-modulated B cell adaptation. This thesis provides both a foundational map of humoral immunity in the tumour microenvironment and one of the first demonstrations that immune-based biomarkers in blood can reveal cancer-associated signals in patients with indeterminate pulmonary nodules, laying the groundwork for immune-informed assays with potential clinical utility in early detection.

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