Spatial single cell dynamics of immune cells in tumours and lymph nodes

Protective immune responses occur in complex tissue ecosystems, we have developed a range of new technologies including Kaede fluorescent protein cellular tracking system, colorectal cancer models and human tissue slice culture systems.  Despite advances in immunoncology, driven by check-point inhibitors, many solid tumours remain refractory to curative therapies. Core to this efficacy failure is the dynamics of antigen specific T cells, in particular the capacity to enter, become resident in the tumour and maintain killing capacity.  Utilising mouse models we have shown that there are two types of lymphocytes, those that transiently enter the tumour and then leave, others that become resident.  Additionally, we have shown that as they become resident, they undergo a metabolic shift leading to inhibition of the immune response.  In this project, we will combine the fluorescent tracking technology with spatial biology (imaging and spatial transcriptomics) to analyse how immune cells adapt in the tumour microenvironment and how targeting tumour stroma can modulate the dynamics of immune responses and link these to human clinical samples.  We will utilise novel bispecific antibodies inducing tertiary lymphoid structures (TLS) to determine if the dynamics and metabolic state of leukocytes entering in the tumour microenvironment can be modulated to drive effector immunology.  We will utilise human and mouse lymph node tissue slice culture system to determine how the immune response can be modulated in the lymph nodes.  Together we will build a 3D atlas of immune cell dynamics in tumours and lymph nodes and how this can be modulated through targeting stromal fibroblasts.

KEYWORDS

Tumour microenvironment, dynamics, pathology, imaging, systems biology

TRAINING OPPORTUNITIES

This interdisciplinary project will involve training in multiplex imaging, spatial transcriptomics, image analysis, in vivo mouse models and human slice culture systems.  A key focus will be on systems biology and data analysis training.

KEY PUBLICATIONS

Dean I, Lee CYC, Tuong ZK, Li Z, Tibbitt CA, Willis C, Gaspal F, Kennedy BC, Matei-Rascu V, Fiancette R, Nordenvall C, Lindforss U, Baker SM, Stockmann C, Sexl V, Hammond SA, Dovedi SJ, Mjösberg J, Hepworth MR, Carlesso G, Clatworthy MR, Withers DR. Rapid functional impairment of natural killer cells following tumor entry limits anti-tumor immunity. Nat Commun. 2024 Jan 24;15(1):683. doi: 10.1038/s41467-024-44789-z.

Lee CYC, Kennedy BC, Richoz N, Dean I, Tuong ZK, Gaspal F, Li Z, Willis C, Hasegawa T, Whiteside SK, Posner DA, Carlesso G, Hammond SA, Dovedi SJ, Roychoudhuri R, Withers DR, Clatworthy MR. Tumour-retained activated CCR7+ dendritic cells are heterogeneous and regulate local anti-tumour cytolytic activity. Nat Commun. 2024 Jan 24;15(1):682. doi: 10.1038/s41467-024-44787-1.

Korsunsky I, Wei K, Pohin M, Kim EY, Barone F, Major T, Taylor E, Ravindran R, Kemble S, Watts GFM, Jonsson AH, Jeong Y, Athar H, Windell D, Kang JB, Friedrich M, Turner J, Nayar S, Fisher BA, Raza K, Marshall JL, Croft AP, Tamura T, Sholl LM, Vivero M, Rosas IO, Bowman SJ, Coles M, Frei AP, Lassen K, Filer A, Powrie F, Buckley CD, Brenner MB, Raychaudhuri S.  Cross-tissue, single-cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases. Med. 2022 Jul 8;3(7):481-518.e14. doi: 10.1016/j.medj.2022.05.002

Croft AP, Campos J, Jansen K, Turner JD, Marshall J, Attar M, Savary L, Wehmeyer C, Naylor AJ, Kemble S, Begum J, Dürholz K, Perlman H, Barone F, McGettrick HM, Fearon DT, Wei K, Raychaudhuri S, Korsunsky I, Brenner MB, Coles M, Sansom SN, Filer A, Buckley CD. Distinct fibroblast subsets drive inflammation and damage in arthritis.  Nature. 2019 Jun;570(7760):246-251. doi: 10.1038/s41586-019-1263-7.

THEMES

Immunology, tumour biology, systems immunology, imaging

CONTACT INFORMATION OF ALL SUPERVISORS

mark.coles2@kennedy.ox.ac.uk

simon.leedham@well.ox.ac.uk

david.withers@immonc.ox.ac.uk

joannah.fergusson@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 13th January 2025.