Investigation of pancreatic immunology during progression of pancreatic ductal adenocarcinoma
Pancreatic ductal adenocarcinoma (PDAC) highly fatal with only 4% of patients surviving 5 years after diagnosis. Therefore, we urgently need to both detect pancreatic cancer earlier and discover better treatments to increase survival rates. To achieve this we need to better understand the biology of the disease and its interaction with microenvironment, in particular the immune cells that normally guard against disease. Recently it has become apparent that cancers in general and pancreatic cancer specifically are capable of mounting an immune response yet the suppressive tumour microenvironment blocks an effective immune response. We are tackling these problems through a variety of approaches 1) by elucidating the cellular biology behind how the cancers form and 2) identifying where the immune-environment of established cancers may vary and therein suggest different therapeutic approaches (e.g. for localised disease where immunological inhibitors and radiation combinations may be successful).
Our previous work has explored how epigenetic inactivation of gene expression (e.g. via DNA methylation) represents an alternative mode of bypassing tumour suppression during cancer onset and progression (Pefani et al. 2014. Nat Cell Biol; Vlahov et al. 2015. Current Biology; Pefani et al. 2016. Mol Cell). Tracking such epigenetic alterations across a range of gastrointestinal cancers (including pancreas) we have found signalling pathways disrupted by epigenetics and now can ask how these alterations alter the immune microenvironment.
Cancers are frequently treated with radiation therapy which paradoxically has both immune stimulatory and immune suppressive effects. We have begun to ask how the immune system affects PDAC and how it can be targeted to improve survival by enhanced radiotherapy (Azad et al. 2017. EMBO Mol Med; D’Costa et al. 2017. Cancer Res).
In this project we will explore the interplay between infiltrating immune cells (e.g. Neutrophils, Macrophages etc.) in the emerging pancreatic tumour environment and how they may influence the epigenetic state of the tumour and surrounding normal stroma. We will aim to utilise mouse models of PDAC and state-of-the-art techniques to evaluate the immune response as well as epigenetic techniques such as ATAC-Seq to define the interplay of immune cells with cellular phenotypes at the single cell level.