Characterising the immunological effects of radiotherapy

Oliver, Jessica 2024. Characterising the immunological effects of radiotherapy. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Background Despite a current focus on the ability of radiotherapy to stimulate an immune-mediated anti-tumour response termed the abscopal effect, there remains a gap in our understanding of the immunobiological mechanisms elicited by the irradiation of cells. To determine how the immune system is impacted by radiotherapy, this study measured immune responses in cancer patients receiving stereotactic ablative radiotherapy (SABR). In parallel, the study characterised the impact of irradiation on the repertoire of class I human leukocyte antigen (HLA-I) peptides, defined as the immunopeptidome. Methods Peripheral blood mononuclear cells and plasma were collected from 31 patients before, during, and after SABR treatment. Using flow cytometry, IFN-g ELISpots, and Luminex, immune composition and antigen-specific T cell responses were explored. Peptide elution and mass spectrometry were utilised to investigate how irradiation modifies the immunopeptidome in terms of peptide number, length, and origin. Results A predominantly immunosuppressive signature of SABR emerged, characterised by a depletion in lymphocytes following treatment. A significant predictor of post-treatment progression was a lymphopenia-induced increase in the neutrophil-to-lymphocyte ratio. Receiving a biological effective dose of >100 Gy or a planning target volume of >25 cc resulted in more drastic lymphopenia and a shorter progression-free survival. This loss in lymphocytes was accompanied by reduced T cell responses to viral and tumour-associated antigens. A unique radiation-induced peptide repertoire emerged, composed of a greater number of peptides, longer peptides with C and/or N terminal extension, and peptides sourced from new proteins, revealing that irradiation alters the potential antigenic landscape of cancer cells. Conclusion Overall, significant radiotherapy-driven immune modulations were observed. Further exploration is now required to understand the mechanisms which account for these changes to identify opportunities for immunotherapy interventions such as combinations with immune checkpoint inhibitors and cancer vaccines to ensure that the positive effects of radiotherapy can be harnessed to increase immune-mediated tumour cell rejection.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Schools > Medicine
Date of First Compliant Deposit:	9 January 2025
Last Modified:	09 Jan 2025 16:40
URI:	https://orca.cardiff.ac.uk/id/eprint/175143

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