Relationship between Tumour microenvironment and atherosclerotic cardiovascular disease during immunotherapy

Tumours actively escape the immune system by inducing an immunosuppressive state where intra-tumoural CD8 T-cells are “exhausted”, expressing an array of checkpoint inhibitory receptors, which results in a lack of effector functions. Immune Checkpoint Blockade (ICB) aims at reinvigorating the immune system and those exhausted T-cells to control tumours by blocking those inhibitory receptors. While it revolutionised treatment for late-stage cancers, cancer patients receiving ICB have a 4.5-fold increased risk for atherosclerotic cardiovascular disease (CVD). The adverse effect of ICB on atherosclerosis-related cardiovascular disease is therefore a major concern, resulting in cardiovascular events, such as myocardial infarction or ischaemic stroke.

The effects of ICB on atherosclerosis in cancer patients are incompletely understood, but emerging data suggests that what is beneficial for anti-tumour immunity is detrimental for ICD. For example, IFNγ, induced following ICB, is required for the efficacy of tumour immunity but has emerged as a significant factor in atherogenesis.

 As such, it is important to understand how ICB integrates with the tumour microenvironment (TME) and the immune landscape of atherosclerotic plaques. In order to do this, we need to establish the relationship between the TME and the atherosclerotic plaque immune landscape.

We will use a model of atherosclerosis whereby atherosclerosis-prone mice (ApoE−/−) will be fed with a high-fat diet (HFD). Those mice will be engrafted with multiple tumour cell lines which generate a different TME. We will analyse the TME, vascular and systemic immune landscape, with a particular interest in macrophages, because they are crucial for both tumour and vascular immunity, and their differentiation is regulated by IFNγ. To do so, we will use imaging, flow cytometry and CYTOF. We will then deplete macrophage subsets that are present in one or both sites and analyse tumour growth in the presence or absence of ICB.

Research Objectives

 i) Characterise whether/how tumours with distinct TMEs influence the systemic immune landscape and the immune landscape of atherosclerotic plaques. We will focus on different macrophage subsets and investigate their role in both the TME and atherosclerosis plaques.

ii) Determine whether the TME influences the severity of artherosclerosis.

iii) Explore the effect of immunotherapy on the TME and its relationship with the immune landscape in artherosclerotic plaques and the effect on the severity of artherosclerosis.

Outcome: This project will unravel the relationship between the tumour microenvironment and the risk of atherosclerosis, both at steady state and during immunotherapy. We hypothesise that immune checkpoint proteins orchestrate the inflammatory response underlying atherogenesis. This will uncover potentially targetable new mechanisms to tackle this type of co-morbidity.

KEYWORDS

Anti-tumour immunity, vascular immunity, checkpoint blockade, CD8 T cells, macrophages

TRAINING OPPORTUNITIES

The student will be based at the Kennedy Institute of Rheumatology which is a world-renowned institute and is housed in a state-of-the-art research facility. This project provides broad training in cancer biology and immunology covering a range of cellular, molecular and functional immune assays. Students have access to cutting-edge technologies such as disease mouse models of cancer, multiplex imaging, spectral flow cytometry, CYTOF. The Gérard Lab and Monaco Lab have complementary skills in tumour and vascular immunology, and are highly collaborative. There is extensive technical support in all techniques required for this project and both labs provide a supportive environment in which PhD students thrive.  

A core curriculum of 20 lectures will be taken in the first term of year 1 to provide a solid foundation in immunology and data analysis. Students will attend weekly departmental meetings and will be expected to attend seminars within the department and those relevant in the wider University. Students will also attend external scientific conferences where they will be expected to present the research findings.

KEY PUBLICATIONS

Lau et al. biorxiv. doi.org/10.1101/2024.03.25.586537.

Mazet JM. et al, (2023), Nature Communications, 14

Headley MB. et al, (2016), Nature, 531, 513 - 517

Nosalski R. et al, (2024), Front Cardiovasc Med, 11

Dib L. et al, (2023), Nature Cardiovascular Research, 2, 853 - 853

THEMES

Immunity, Inflammation

CONTACT INFORMATION OF ALL SUPERVISORS

audrey.gerard@kennedy.ox.ac.uk

claudia.monaco@kennedy.ox.ac.uk

The Kennedy Institute is a proud supporter of the Academic Futures scholarship programme, designed to address under-representation and help improve equality, diversity and inclusion in our graduate student body.  The Kennedy and the wider University rely on bringing the very best minds from across the world together, whatever their race, gender, religion or background to create new ideas, insights and innovations to change the world for the better. Up to 50 full awards are available across the three programme streams, and you can find further information on each stream on their individual tabs (Academic futures | Graduate access | University of Oxford).

How to Apply

Please contact the relevant supervisor(s), to register your interest in the project, and the departmental Education Team (graduate.studies@ndorms.ox.ac.uk), who will be able to advise you of the essential requirements for the programme and provide further information on how to make an official application. 

Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form is found online and the DPhil or MSc by research will commence in October 2025.

Applications should be made to the following programme using the specified course code. 

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1) 

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.

Interviews to be held week commencing 13^th January 2025.