Investigating the epigenetic effects of chronic inflammation with respect to cancer immunity

Lead Research Organisation: University of Oxford
Department Name: Oncology

Abstract

Chronic inflammation is associated with suppression of immunity and promotion of cancer. How cancer triggers impaired immunity and how an immunosuppressed state is maintained in cancer is unclear however. Cancer has previously been associated with differential DNA methylation in whole blood. Data we have generated highlights specific inflammatory stimuli are associated with particular epigenetic phenomena including differential DNA methylation. We have identified thousands of sites across the genome which are differentially methylated in response to inflammatory stimuli ex vivo.
It is unknown though whether inflammation per se drives cancer associated DNA methylation changes in blood. Moreover, this whole blood signature reflects a composite of effects across different cell subsets - the specific immune cell subsets most affected by cancer remain unknown.
This project focuses upon exploring the epigenetic consequences of cancer within the immune system.
Objectives/Aims
1. Identification of methylation signatures reflective of exposure to different inflammatory cytokines across lymphoid and myeloid cells
2. Investigate the effects of different cancers upon DNA methylation across immune cell subsets with a view to identifying the subsets most sensitive to cancer and de-convoluting key driver inflammatory stimuli
3. Investigate the persistence of cancer associated DNA methylation changes - do these resolve with treatment?

Publications

10 25 50

Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509711/1 01/10/2016 30/09/2021
1963686 Studentship EP/N509711/1 01/10/2017 30/09/2021 Chelsea Taylor
 
Description Data obtained in my first year contributed to the understanding of a type of monocyte (immune cell) involved in autoimmune disease (Al-Mossawi et al, Nature Communications, 2019). My work looked at gene expression associated with a specific subset of monocyte highly enriched in spondyloarthritis patients. Additionally, I looked into the genetic effects of some of these genes by comparing monocyte gene expression between individuals of different genotype at the single cell level.

My second year involved in broad phenotyping peripheral blood from metastatic melanoma patients receiving immune checkpoint immunotherapy using several approaches including flow cytometry. I helped my supervisor draft and write a paper and contributed much of my data. Together, we described the transcriptomic effect of peripheral CD8+ T-cells after immune checkpoint inhibitor therapy and found several genes, including T-cell receptor genes, to be associated with clinical outcome (Fairfax BP et al, Nature Medicine, 2020). I investigated many of these T-cell receptors and validated bioinformatic deconvolution of T-cell receptor usage and characterised gene expression of expanding clones at the single cell level. We went on to find that large clones associate with clinical response. I combined my flow cytometry data with the transcriptomic and found that these large clones have a more effector memory-like phenotype.

Further transcriptomic and flow cytometry analysis have identified a specific T-cell subtype that strongly associates with clinical outcome. I have investigated this further in my third year and this work is currently being drafted for publication.
Exploitation Route Our lab all work on identifying predictive markers and describing response to immune checkpoint inhibitors in a large cohort of metastatic melanoma patients (>180 patients, >500 samples). We each investigate different aspects of the peripheral immune compartment and correlate our data with each other. With immune checkpoint inhibitors gaining international recognition winning the Nobel Prize for Physiology or Medicine in 2018 and being approved for use in the clinic, it's important to identify predictive markers of clinical response and associated side effects. This can help guide patient treatment and describe the mechanism of action of the therapy.
Sectors Healthcare

 
Title Transcriptomic data available online 
Description Data from transcriptomic analysis of CD8+ T-cells in a large cohort of metastatic melanoma patients pre- and post-immune checkpoint inhibitor therapy and our subsequent paper (Fairfax BP et al, Nature Medicine, 2020) is available online. Our analysis technique in the form of coding scripts is also available. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact Publication: Fairfax BP et al, Nature Medicine, 2020 Other researchers have requested its use to look in their own data and take a similar approach. 
URL https://www.nature.com/articles/s41591-019-0734-6
 
Description Advice and bioinformatic support between different research groups 
Organisation John Radcliffe Hospital
Department Department of Gastroenterology
Country United Kingdom 
Sector Hospitals 
PI Contribution We helped them by analysing much of their large genetic data and in return, they provided us with their expertise on a small subset of T-cell and helped guide my experiments.
Collaborator Contribution They gave us lots of advice on a small subset of T-cell and helped decide which direction to take the project. They guided our experimental design and they also provided many of the reagents that I required.
Impact This work is still under way. I am currently drafting a manuscript of the findings for publication.
Start Year 2019
 
Description Collaboration between different research groups to integrate bioinformatic and rheumatology experience 
Organisation University of Oxford
Department Botnar Research Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution We helped with bioinformatic genetic analysis of their large datasets and validated many of their findings with different techniques using our own expertise.
Collaborator Contribution They provided most of the data and funded a large part of my experiments.
Impact Publication: Al-Mosswai H et al, Nature Communications, 2019
Start Year 2018
 
Description In2Science school student Oncology day organiser and volunteer 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact The charity In2Science funded several school students to work in a lab and get work experience at our research institute. Each department had an event to explain about their area and organised fun activities. I was on the development team for the Oncology day and organised a lecture, teaching about various aspects of oncology and designed fun activities and challenges per section. This event helped these school students decide if they wanted to pursue a career in research.
Year(s) Of Engagement Activity 2020
 
Description MRC Festival of Medical Research 2018 development team and volunteer 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact As part of the MRC Festival of Medical research 2018, a team of researchers at our institute organised several events across Oxfordshire. We designed a stand, various activities and leaflets/posters to communicate the research that our institute is involved in as well as around the world. This year we explained about "Gene editing". This activity was also taken to the Family fun day at the UK Research and Innovation Centre in London, several Oxford science festivals and schools.
Year(s) Of Engagement Activity 2018
URL https://www.imm.ox.ac.uk/about/news/taking-science-to-the-supermarket
 
Description MRC Festival of Medical Research 2019 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact As part of the MRC Festival of Medical research 2019, a team of researchers at our institute organised several events across Oxfordshire. We designed a stand, various activities and leaflets/posters to communicate the research that our institute is involved in as well as around the world. This year we explained about "Cancer immunotherapy". This activity was also taken to several Oxford science festivals, schools and an event for underprivileged school students. We also spoke to our local MP about the work and research that we do at the Institute.
Year(s) Of Engagement Activity 2020
URL https://www.imm.ox.ac.uk/about/news/mrc-wimm-researchers-take-their-research-on-new-cancer-therapy-t...
 
Description Oxford Science and Ideas Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact We took our "Gene editing" stand and activities from Oxford's MRC Festival of Medical Research 2018 and 2019 and took them to Oxford Science Festival. We engaged with the public about cutting-edge research, the science behind it and how it may affect healthcare. On each occasion, we talked about "Gene editing" or "Cancer immunotherapy", 2 ground-breaking therapies applicable for a variety of diseases. We hope to have informed them about what medical research the MRC funds, what we are doing at our institute and to change their opinion of science.
Year(s) Of Engagement Activity 2020
 
Description UK Research and Innovation Centre London Family Fun Day organiser and volunteer 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact We initially took this activity to the Oxford MRC Festival of Medical Research 2018 and were invited by them to present at the UK Research and Innovation Centre in London Family Fun day. This was a fun day with several stands aimed at educating families about different areas of science in a fun and comprehensive way.
Year(s) Of Engagement Activity 2020