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Download StatisticsBuchanan, Richard James (2021). Exploring the immune signature of lung adenocarcinoma: examining RORγT expression in KRAS and STK11 mutant tumours. University of Birmingham. Ph.D.
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Buchanan2021PhD.pdf
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Abstract
Lung adenocarcinoma (LUAD) is a common subtype of non-small-cell lung carcinoma that is driven by somatic mutations in various cancer genes. Intratumoural immunity is linked to tumour genetics and can influence response to treatment. Examining LUAD data from The Cancer Genome Atlas (TCGA), we delineated immune gene expression signatures for tumours with mutations in 11 different key cancer genes including KRAS and STK11. Although both these groups had generally low immune gene expression, each demonstrated significantly increased RORC mRNA expression, which encodes the T helper 17 (Th17) transcription factor RORγT. Using a unique cohort of mutationally profiled tumour resections, we found significantly higher intratumoural RORγT\(^+\) lymphocytes by immunohistochemistry in LUADs with these mutations, many of which bordered tertiary lymphoid structures. Multiplex immunohistochemistry revealed that these lymphocytes were largely Th17s, and elevated intratumoural RORγT\(^+\) lymphocytes were associated with poor overall survival. We subsequently developed an in vitro system in which T cells were cultured in media conditioned by lung carcinoma cell lines and found suppressed or regulatory CD3\(^+\)/CD4\(^+\)/RORγT\(^+\) T cells were present in conditioned media from cell lines with loss of STK11 function. These findings show that cancer gene mutations can influence tumour immunity and have important implications for stratified immunotherapy.
| Type of Work: | Thesis (Doctorates > Ph.D.) | |||||||||
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| Award Type: | Doctorates > Ph.D. | |||||||||
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| Licence: | All rights reserved | |||||||||
| College/Faculty: | Colleges (2008 onwards) > College of Medical & Dental Sciences | |||||||||
| School or Department: | Institute of Immunology and Immunotherapy | |||||||||
| Funders: | Other | |||||||||
| Other Funders: | British Lung Foundation | |||||||||
| Subjects: | Q Science > QR Microbiology > QR180 Immunology | |||||||||
| URI: | http://etheses.bham.ac.uk/id/eprint/12080 |
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