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Analysing immune responses to metastatic ovarian tumours to identify therapeutic targets


About This PhD Project

Project Description

Research interests/description of main research theme:
Ovarian cancer remains the most lethal gynaecological malignancy for women over 50 years old (1). Due to the difficulty of diagnosing the disease at early stages, seventy to eighty percent of ovarian cancer patients present with advance disease carrying several tumours around the abdominal cavity (2). The metastatic tumours appear to form in pre-existing clusters of immune cells embedded in omental and mesenteric adipose tissues called fat associated lymphoid clusters (FALCs)/milky spots (3-4). The immune responses to ovarian tumours and peritoneal metastasis remain poorly characterized.
Our group had shown that FALCs are local hubs of innate and adaptive immune cells on a network of fibroblastic stromal cells that respond very fast to inflammation and infection by inducing the recruitment of large number of immune cells and supporting their interactions (4-5). We have recently used animal models of colon and ovarian cancer that replicate metastatic tumour formation in patients to show that FALCs act as pre-metastatic niches for these tumours. Colon and ovarian tumours induced an immunosuppressive environment that prevented anti-tumour responses.
The aim of this project is to analyse the immune responses to ovarian tumours using a novel orthotopic animal model and to investigate the effects of activating the innate immune system in the development of anti-tumour responses.
The student will employ animal models of ovarian and colon cancer to elucidate the tumour-induced effects in the immune microenvironment and to identify pathways that can be activated/inhibited to block immunosuppression and induce anti-tumour responses. A particular emphasis of the project will be the characterization of tumour infiltrating lymphocytes (TILs) with a focus on CD8+ T cells and Tregs, the main players mediating immune responses to the tumours. In addition a detailed study of the characteristics of the antigen presenting cells in tumours and the associated metastatic tissues will be carried out to elucidate the role of these cells in supporting anti-tumour responses.
Deciphering the immune responses to ovarian tumours and metastasis will facilitate the identification of putative therapeutic targets to induce long lasting anti-tumour responses.
The student will utilize multi-colour flow cytometry analysis, immunofluorescence staining and confocal microscopy and single cell gene expression approaches to analyse the immune microenvironment in fresh tumour tissues.
This project is a collaborative effort between the groups of David Withers, with a long standing expertise in immune responses to tumours in animal models and Jorge Caamano with expertise in the interactions between immune and stromal cells in adipose tissues in development, inflammation and immune responses. The groups are located in the Institute for Biological Research at the College of Medical and Dental Sciences of UoB where they have access to state of the art equipment and facilities including multicolor flow cytometry, high speed cell sorting and confocal, multi-photon and light sheet microscopes. The combined expertise of the applicants will provide the critical mass for the success of this project.

Person Specification
We are looking for outstanding students with a strong background in immunology, and ideally a focus in T cells and antigen presenting cells. An interest in bioinformatics will be a plus. They should have a commitment to research in immune responses to cancer and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

How to apply
Applications should be directed to Jorge Caamano (email ). To apply, please send:
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.

References

1. Coburn S, et al. (2017). International patterns and trends in ovarian cancer incidence, overall and by histologic subtype. Int J Cancer. 140: 2451

2. Lengyel E. (2010) Ovarian cancer development and metastasis. Am J Pathol 177:1053.

3. Moro K, et al (2010) Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463: 540

4. Benezech C, et al. (2015) Inflammation-induced formation of fat-associated lymphoid clusters. Nat Immunol 16:819

5. Cruz Migoni S, et al. (2016) Fat-Associated Lymphoid Clusters in Inflammation and Immunity. Front Immunol. 7:612.

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