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Title: The immune response to DNA damage
Author: Parkes, Eileen
ISNI:       0000 0004 6059 5245
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2016
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Breast cancer is a highly heterogenous disease and current methods of treatment selection in the clinic do not take account of this heterogeneity. In order to improve outcomes in breast cancer, a personalised approach is required. Previously we identifed a DNA damage response deficient (DDRD) molecular subgroup within breast cancer. A 44-gene expression assay prospectively identifying this subgroup was validated as predicting benefit from DNA-damaging chemotherapy. This subgroup was defined by interferon signalling. In this study the biology identified by the subgroup is addressed, identifying activation of the cytosolic DNA-sensing innate immune pathway cGAS/STING/TBK1/IRF3 in DNA damage response deficient cancer cells. This study highlights the importance of this pathway in cancer cell chemokine production. Importantly, activation of this pathway is cell-cycle related and can be induced by exogenous S-phase DNA damage. We characterise the immune infiltrate in DNA damage response deficient breast tumours, identifying both anti-tumourigenic and pro-tumourigenic immune cell populations. Also, expression of the immune checkpoint protein PD-L1 is identified as upregulated in DDRD assay positive breast tumours. These data indicate that tumours with an endogenous DNA damage response deficiency employ expression of immune checkpoints as a means of immune escape. Therefore, immune checkpoints are important therapeutic targets in this subgroup of breast cancer. In addition, we present preliminary analysis of a clinical trial designed to assess the feasibility of using the 44-gene expression assay in predicting response to neoadjuvant chemotherapy in breast cancer. Given our findings, we identify potential targets in DNA damage response deficient tumours, combination strategies with anti-PD-1/PD-L1 targeted therapies and provide evidence for the prospective utility of the DDRD gene expression assay in predicting response to DNA damaging chemotherapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available