Title: Understanding the DNA Damage Driven Immune Response in Breast Cancer: Opportunities for Improved Stratification and Treatment
Funder: Cancer Research UK

Abstract: BACKGROUND A significant proportion of breast cancers exhibit a DNA double strand break repair (DSBR) deficiency and are genomically unstable. Evidence suggests that genomic instability may correlate with response to immune checkpoint inhibition. This has been attributed to accumulation of mutations resulting in neo-antigen expression, leading to an immune response, which is inhibited by immune checkpointing proteins such as PD-L1. However, we have reported an additional mechanism for immune activation in DSBR-deficient breast cancers and identified a distinct molecular subtype within these tumours through gene expression profiling. This signature is characterised by activation of IRF3-mediated immune genes, identifying patients who respond to DNA-damaging chemotherapy. Mechanistically, the DNA damage response deficiency (DDRD) signature is driven by cytoplasmic DNA, which is sensed by the cGAS/STING pathway, resulting in IRF3 activation. The signature has been validated in several independent datasets, including our recent prospective Neo-DDRD clinical trial. Additionally, we have found that this signature is “switched on” in response to DNA damage, suggesting that therapeutic challenge with DNA-damaging chemotherapies may sensitise tumours to immune checkpoint blockade. AIMS The aim of this programme is to further investigate the biology underpinning the DDRD/immune-response by addressing the following clinically applicable questions: 1. What therapeutic agents can activate the DDRD/immune-response? 2. What pathways/factors participate in the activation of the DDRD-immune response? METHODS We will combine RNA-Seq analysis of breast tumour samples pre- and post-chemotherapy with immunohistochemical studies along with cell biology, in-vitro drug screening and syngeneic mouse modelling to answer these questions. Specifically, we will assess induction of DDRD/immune-biology and immune cell infiltration in tumour samples following treatment with classical DNA-damaging chemotherapy. Additionally, we will use a targeted drug screen in combination with high-content microscopy to identify approved drugs that activate DDRD/immune-biology. These drugs may render immune “cold” tumours susceptible to immune checkpoint inhibiting therapies. Finally, we will use a combination of high-content imaging, targeted siRNA screening and cell biology to identify pathways involved in the activation of DDRD-immune signature. HOW THE RESULTS OF THIS RESEARCH WILL BE USED The identification of drugs that activate DDRD/immune-biology may lead to rational combinations with immunomodulatory agents. Furthermore, improved understanding of the biological and immunological responses to treatment will allow identification and validation of much-needed pharmacodynamic biomarkers with clinical utility in the immune-oncological setting. Finally, elucidating the mechanisms involved in modulating the DDRD/immune-response may identify novel drug targets for the treatment of DDR deficient/innate immune positive breast cancers.


Research activity codes: 5.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS