Antibodies, B cells, and immune tolerance in immunotherapy treated oesophageal cancer
Oesophageal cancer (OC) is a leading cause of cancer mortality that is rapidly rising in prevalence in many parts of the world. Immune checkpoint inhibitors (ICI) have revolutionised treatment of many cancer types and were recently approved by the FDA to treat advanced OC. However, there are still m...
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| Format: | Thesis |
| Language: | English |
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2022
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| _version_ | 1826311942405357568 |
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| author | Chadwick, J |
| author2 | Lu, X |
| author_facet | Lu, X Chadwick, J |
| author_sort | Chadwick, J |
| collection | OXFORD |
| description | Oesophageal cancer (OC) is a leading cause of cancer mortality that is rapidly rising in prevalence in many parts of the world. Immune checkpoint inhibitors (ICI) have revolutionised treatment of many cancer types and were recently approved by the FDA to treat advanced OC. However, there are still many patients who do not exhibit an improved outcome in response to ICI therapy, and predictive biomarkers are lacking. Studies of multiple cancer types have shown that development of immune related adverse events (irAEs) during ICI treatment is associated with good clinical outcome, suggesting that the baseline immune activation of an individual may influence their response. Similarly, the presence of tertiary lymphoid structures, which are sites in which B cells differentiate into antibody secreting cells, in tumours hasrecently been shown to predict improved clinical outcome to ICI treatment, suggesting that production of tumour-reactive antibodies by intra-tumour B cells may contribute to an effective anti-tumour immune response. Despite this, there is a lack of studies of ICI treated OC which either evaluate markers of baseline immune activation, such as autoantibodies (AAbs), as predictive biomarkers of clinical outcome, or characterise antibodies produced by intratumour B cells. In this thesis, I extensively profile the circulating AAbs and peripheral blood mononuclear cells (PBMCs) of ICI treated OC patients from the LUD2015-005 clinical trial to identify novel and distinct signatures predictive of good clinical outcome and development of irAEs during ICI treatment. Further, through transcriptional profiling of OC tumours I show evidence of fully mature B cell responses and identify B cells expressing tumour-reactive antibodies. In summary, this work characterises the role of baseline immune activation in ICI patient clinical outcomes, and expands our understanding of mechanisms that predispose to good clinical outcome or irAE development during ICI treatment. The validation of these results in larger independent cohorts could inform patient treatment decisions based on biomarkers predictive of clinical outcome. |
| first_indexed | 2024-03-07T08:20:13Z |
| format | Thesis |
| id | oxford-uuid:72eab943-8247-4d8c-922d-de98817e45ab |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T08:20:13Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | oxford-uuid:72eab943-8247-4d8c-922d-de98817e45ab2024-01-23T11:36:43ZAntibodies, B cells, and immune tolerance in immunotherapy treated oesophageal cancerThesishttp://purl.org/coar/resource_type/c_db06uuid:72eab943-8247-4d8c-922d-de98817e45abImmunologyClinical trialsB cellsAutoantibodiesCancerEnglishHyrax Deposit2022Chadwick, JLu, XDustin, LOesophageal cancer (OC) is a leading cause of cancer mortality that is rapidly rising in prevalence in many parts of the world. Immune checkpoint inhibitors (ICI) have revolutionised treatment of many cancer types and were recently approved by the FDA to treat advanced OC. However, there are still many patients who do not exhibit an improved outcome in response to ICI therapy, and predictive biomarkers are lacking. Studies of multiple cancer types have shown that development of immune related adverse events (irAEs) during ICI treatment is associated with good clinical outcome, suggesting that the baseline immune activation of an individual may influence their response. Similarly, the presence of tertiary lymphoid structures, which are sites in which B cells differentiate into antibody secreting cells, in tumours hasrecently been shown to predict improved clinical outcome to ICI treatment, suggesting that production of tumour-reactive antibodies by intra-tumour B cells may contribute to an effective anti-tumour immune response. Despite this, there is a lack of studies of ICI treated OC which either evaluate markers of baseline immune activation, such as autoantibodies (AAbs), as predictive biomarkers of clinical outcome, or characterise antibodies produced by intratumour B cells. In this thesis, I extensively profile the circulating AAbs and peripheral blood mononuclear cells (PBMCs) of ICI treated OC patients from the LUD2015-005 clinical trial to identify novel and distinct signatures predictive of good clinical outcome and development of irAEs during ICI treatment. Further, through transcriptional profiling of OC tumours I show evidence of fully mature B cell responses and identify B cells expressing tumour-reactive antibodies. In summary, this work characterises the role of baseline immune activation in ICI patient clinical outcomes, and expands our understanding of mechanisms that predispose to good clinical outcome or irAE development during ICI treatment. The validation of these results in larger independent cohorts could inform patient treatment decisions based on biomarkers predictive of clinical outcome. |
| spellingShingle | Immunology Clinical trials B cells Autoantibodies Cancer Chadwick, J Antibodies, B cells, and immune tolerance in immunotherapy treated oesophageal cancer |
| title | Antibodies, B cells, and immune tolerance in immunotherapy treated oesophageal cancer |
| title_full | Antibodies, B cells, and immune tolerance in immunotherapy treated oesophageal cancer |
| title_fullStr | Antibodies, B cells, and immune tolerance in immunotherapy treated oesophageal cancer |
| title_full_unstemmed | Antibodies, B cells, and immune tolerance in immunotherapy treated oesophageal cancer |
| title_short | Antibodies, B cells, and immune tolerance in immunotherapy treated oesophageal cancer |
| title_sort | antibodies b cells and immune tolerance in immunotherapy treated oesophageal cancer |
| topic | Immunology Clinical trials B cells Autoantibodies Cancer |
| work_keys_str_mv | AT chadwickj antibodiesbcellsandimmunetoleranceinimmunotherapytreatedoesophagealcancer |