Understanding the immunosuppressive role of fibroblast and macrophages in ovarian cancer.

Oncolytic viruses (OVs) preferentially infect and kill cancer cells, and their clinical efficacy has been demonstrated against a number of different cancers. The most clinically advanced OV is a genetically engineered herpes simplex virus (T-VEC) which expresses GMCSF to aid the development of anti-tumour immune responses; T-VEC is approved for the treatment of metastatic melanoma. OVs use multiple mechanisms to induce their anti-cancer effects including: (i) preferential viral replication in cancer cells and subsequent cell death - a process known as oncolysis; and (ii) stimulation of both innate and adaptive anti-tumour immune responses capable of eradicating malignant cells. However, the tumour microenvironment comprises a complex network of cell-cell interactions, and multiple mechanisms exist which support tumour growth and inhibit anti-cancer immune responses. These include the release of cancer promoting growth factors and cytokines from tumour stroma and inhibition of anti-cancer cytotoxic T lymphocytes (CTLs) and natural killer (NK) cell by cancer-associated fibroblast (CAF) and tumour-associated macrophages (TAMs). In recent years, a greater understanding of the tumour microenvironment has enabled researchers to design complementary combination therapies which enhance OV efficacy. However, greater understanding of the immunosuppressive mechanisms utilised by CAF and TAMs in ovarian cancer is required to enhance the efficacy of OV-based immunotherapies in ovarian cancer. <br /> This PhD project will characterise immunosuppressive mechanisms utilised by CAF and TAM in ovarian cancer and develop strategies to overcome these to enhance the efficacy of OV-based immunotherapies. Novel therapeutic strategies could include the inhibition of immunosuppressive networks using siRNA technologies, to abrogate inhibitory factors within the tumour microenvironment, or OV-drug combinations. This work will be carried out using established in vitro human model systems and has the potential to progress to in vivo studies. Ultimately, this project will generate novel strategies to increase the efficacy of OV anti-cancer therapy in ovarian cancer. Moreover, this project also has the potential to inform the application of OV-based immunotherapy in alternative cancer types.

<h2 style="text-align: justify;"><strong>Techniques associated with project:</strong></h2> <p style="text-align:justify">During this PhD project students will learn a range of cellular and molecular biology techniques including 2D and 3D cell culture models; viral propagation and infection; siRNA transfection; cell viability assays; ELISA; RT-PCR and flow cytometry. Importantly, there will also be an opportunity to gain in vivo experience, if desired by the appointed PhD student.  These skills provide a solid basis to pursue a career in most biology fields but the appointed student will develop background knowledge and specific expertise that is particularly relevant to a career in cancer research, cancer biology and/or cancer immunology.</p> <p style="text-align:justify"> </p> <h2 style="text-align: justify;"><strong>REFERENCES: </strong></h2> <p style="text-align:justify"> </p> <ol> <li style="text-align: justify;">Müller LME, Holmes M, Michael JL, Scott GB, West EJ, Scott KJ, Parrish C, Hall K, Stäble S, Jennings VA, Cullen M, McConnell S, Langton C, Tidswell EL, Shafren D, Samson A, Harrington KJ, Pandha H, Ralph C, Kelly RJ, Cook G, Melcher AA, Errington-Mais F. (2019) <a href="https://www.ncbi.nlm.nih.gov/pubmed/31262361">Plasmacytoid dendritic cells orchestrate innate and adaptive anti-tumor immunity induced by oncolytic coxsackievirus A21.</a> J Immunother Cancer. Jul 1;7(1):164.</li> <li><a href="https://pubmed.ncbi.nlm.nih.gov/35393414/">Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy.</a> Wedge ME, Jennings VA, Crupi MJF, Poutou J, Jamieson T, Pelin A, Pugliese G, de Souza CT, Petryk J, Laight BJ, Boileau M, Taha Z, Alluqmani N, McKay HE, Pikor L, Khan ST, Azad T, Rezaei R, Austin B, He X, Mansfield D, Rose E, Brown EEF, Crawford N, Alkayyal A, Surendran A, Singaravelu R, Roy DG, Migneco G, McSweeney B, Cottee ML, Jacobus EJ, Keller BA, Yamaguchi TN, Boutros PC, Geoffrion M, Rayner KJ, Chatterjee A, Auer RC, Diallo JS, Gibbings D, tenOever BR, Melcher A, Bell JC, Ilkow CS.Nat Commun. 2022 Apr 7;13(1):1898. doi: 10.1038/s41467-022-29526-8.PMID: 35393414 </li> <li><a href="https://pubmed.ncbi.nlm.nih.gov/31053413/">Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition.</a> Jennings VA, Scott GB, Rose AMS, Scott KJ, Migneco G, Keller B, Reilly K, Donnelly O, Peach H, Dewar D, Harrington KJ, Pandha H, Samson A, Vile RG, Melcher AA, Errington-Mais F.Mol Ther. 2019 Jun 5;27(6):1139-1152. doi: 10.1016/j.ymthe.2019.04.008. Epub 2019 Apr 14. PMID: 31053413 </li> </ol>

<p>Formal applications for research degree study should be made online through the <a href="https://www.leeds.ac.uk/research-applying/doc/applying-research-degrees">University's website</a>. Please state clearly in the research information section that the research degree you wish to be considered for is U<strong>nderstanding the immunosuppressive role of fibroblast and macrophages in ovarian cancer</strong> as well as <strong>Dr Fiona Errington-Mais and Dr Victoria Jennings </strong>as your proposed supervisor.</p> <p>If English is not your first language, you must provide evidence that you meet the University's minimum English language requirements (below).</p> <p><em>As an international research-intensive university, we welcome students from all walks of life and from across the world. We foster an inclusive environment where all can flourish and prosper, and we are proud of our strong commitment to student education. Across all Faculties we are dedicated to diversifying our community and we welcome the unique contributions that individuals can bring, and particularly encourage applications from, but not limited to Black, Asian, people who belong to a minority ethnic community, people who identify as LGBT+ and people with disabilities. Applicants will always be selected based on merit and ability.</em></p>

Applicants to research degree programmes should normally have at least a first class or an upper second class British Bachelors Honours degree (or equivalent) in an appropriate discipline. The criteria for entry for some research degrees may be higher, for example, several faculties, also require a Masters degree. Applicants are advised to check with the relevant School prior to making an application. Applicants who are uncertain about the requirements for a particular research degree are advised to contact the School or Graduate School prior to making an application.

The minimum English language entry requirement for research postgraduate research study is an IELTS of 6.5 overall with at least 6.0 in each component (reading, writing, listening and speaking) or equivalent. The test must be dated within two years of the start date of the course in order to be valid. Some schools and faculties have a higher requirement.

<p>For further information please contact the Graduate School Office<br /> e: <span style="font-size:11.0pt"><span style="font-family:"Calibri",sans-serif"><span style="color:black"><a href="mailto:fmhpgradmissions@leeds.ac.uk" style="color:#0563c1; text-decoration:underline">fmhpgradmissions@leeds.ac.uk</a></span></span></span></p>