PhD Studentship: Dissecting the dynamic changes in the innate immune cells of tumours to enhance im

Aims

We will utilise models of in vivo cellular migration to reveal new understanding of tumour infiltrating immune cells. Focusing on the innate immune response, we will establish a detailed order of how the innate composition of the tumour microenvironment is established and how it changes both over time and in response to different therapeutic interventions targeting T cell checkpoint mechanisms. We will seek to identify key mechanisms controlling recruitment and retention of innate immune cells into tumours.

Project details

Photoconvertible transgenic mice enable the use of violet light to label cells at a specific site and thus directly assess cellular migration in vivo (Tomura et al., 2008). We recently established an approach to temporally label all the cells within a peripheral lymph node and then assess cellular migration into and out of this tissue (Marriott et al., 2017). How cells are recruited and retained within tumours is a fundamental question in tumour immunology and understanding of these processes offers new opportunities to disrupt the immunosuppressive environment of the tumour. Through photoconversion of a tumour draining lymph node or the tumour itself, we reason that tumour infiltrating lymphocytes and other immune cells can be specifically labelled in a temporal manner. Specifically, cells that had only recently entered the tissue could be distinguished and dynamic phenotypic changes after tumour entry could be determined.

Through analysing expression of cells retained in the tumour or exiting the tumour for the periphery, molecules affecting retention can be identified. Furthermore, this system can then be utilised to compare dynamic changes induced by current treatments and with understanding the surface expression changes in different molecules, devise new combination strategies to enhance anti-tumour responses.

It is evident that innate immune cell populations in tumours contribute to an immunosuppressive environment. The Withers lab has focused on the role of innate lymphoid cells (ILCs) in manipulating adaptive immune responses for many years. Several studies have identified different ILC populations in tumours, but whether these cells are beneficial or suppressive is far from clear. Furthermore, ILC expression of molecules such as PDL1 and PD1 indicates these cells may be affected by checkpoint inhibition. ILC populations in tumours will be investigated and compared with other innate immune cell populations such as MDSCs, well established as key cells that limit anti-tumour responses. The innate compartment is also dependent upon the type and site of the tumour and multiple in vivo tumour models will be assessed. From these initial broad characterisations, the project will then drill down into specific innate immune cell populations and explore their migratory properties.

This is an exciting opportunity to experience research in the highly relevant field of immuno-oncology. This studentship is supported by an established and close collaboration with MedImmune, industrial leaders in therapies targeting checkpoint blockade. The successful applicant will receive excellent training in basic in vivo research and benefit from both academic and industrial supervisors. The project includes a fully funded placement for up to 6 months with MedImmune. The studentship will involve substantial in vivo work and rely heavily on flow cytometry, alongside immunofluorescence, and other techniques such as qPCR.

 

Person Specification

Applicants should have a strong background in biomedical sciences, and ideally a background and strong interest in immunology and/or oncology. They should have a commitment to in vivo research to better understand immune responses and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

To apply and for full eligibility please complete the application form.

Funding Notes

This is an MRC iCASE studentship. The successful student will be paid an annual stipend, tuition fees will be paid and an allowance for a laptop is available. Further details available at https://www.birmingham.ac.uk/schools/mds-graduate-school/scholarships/mrc-impact/index.aspx

References

Marriott CL, Dutton EE, Tomura M, Withers DR. 2017. Retention of Ag-specific memory CD4+ T cells in the draining lymph node indicates lymphoid tissue resident memory populations. Eur J Immunol. 47(5):860-871.

Tomura, M., Yoshida, N., Tanaka, J., Karasawa, S., Miwa, Y., Miyawaki, A. and Kanagawa, O., Monitoring cellular movement in vivo with photoconvertible fluorescence protein "Kaede" transgenic mice. Proc Natl Acad Sci U S A 2008. 105: 10871-10876.

Mackley EC, Marriott CL, Cerovic V, Houston S, Filbey KJ, Maizels RM, Milling S, Withers DR. 2015. CCR7-dependent trafficking of RORgamma(+) ILCs creates a unique microenvironment within mucosal draining lymph nodes. Nat Commun. 6:5862.