Sahwangarrom, Teerapon;
(2026)
Defining preinvasive remodelling of CD4 T cell differentiation to intercept lung squamous carcinogenesis.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Lung cancer is the leading cause of cancer death worldwide, with late-stage disease accounting for the majority of diagnoses, underscoring the urgent need for improved early detection and prevention technologies. T cell responses are initiated and dysregulated during early carcinogenesis, providing a basis for immune-focused early cancer detection and interception strategies. Here, we profiled pre-invasive lesions of human and murine airways to examine whether early T cell reprogramming during lung squamous cell carcinoma (LUSC) progression could be exploited for the early detection and precision immunoprevention of lung cancer. Here, I performed scRNAseq analysis of human pulmonary carcinoma-in-situ (CIS) lesions and adjacent normal lung tissue. In our primary UCLH bronchoscopy cohort, we discovered that CIS lesions are characterised by an early expansion of highly suppressive BATF+Helios+OX40+GITR+ICOS+CD177+ Treg cells (‘BATF Tregs’, n=16 samples, 7 patients). We validated this result in a scRNAseq meta- analysis of 457 samples from 251 patients, and bulk gene expression data of 122 bronchial biopsies from 77 patients. BATF+Tregs were also associated with resistance to anti-PD-1 in the advanced setting using publicly available data, independent of mutational burden and overall infiltration (n=195). Within CIS lesions, clonal tracking identified that BATF+Tregs likely emerged from local expansion, in situ differentiation from stem-like progenitor pools and infiltration of effector Tregs from the circulation. This result led to my team finding that circulating effector Tregs could be used to track and predict preinvasive disease progression in the blood of individuals undergoing bronchoscopy and CT screening, providing a platform for early detection under patent. Using scRNAseq to analyse lung, blood and draining lymph nodes from a carcinogen-driven mouse model of LUSC carcinogenesis, I found that Batf+Tregs and systemic effector Tregs were significantly increased during preinvasive progression in vivo, recapitulating our results from human LUSC development. Finally, I discovered pathways to support immune interception of Batf+Treg differentiation, one of which has been functionally validated by my team. These data suggest that preinvasive BATF+Tregs could be tracked and targeted to provide a novel platform for interception of LUSC in those at risk.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Defining preinvasive remodelling of CD4 T cell differentiation to intercept lung squamous carcinogenesis |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2026. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. // This thesis has been publicly available in UCL Discovery since 23 February 2026. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10220391 |
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