About the Project
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 breast cancer is required to enhance the efficacy of OV-based immunotherapies in breast cancer.
This PhD project will characterise immunosuppressive mechanisms utilised by CAF and TAM in breast 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 or miRNA technologies and/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 breast cancer. Moreover, this project also has the potential to inform the application of OV-based immunotherapy in alternative cancer types.
Techniques associated with this project:
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.
This project is part of the International PhD Academy: Medical Research
You should hold a first degree equivalent to at least a UK upper second class honours degree in a relevant subject.
Candidates whose first language is not English must provide evidence that their English language is sufficient to meet the specific demands of their study. The Faculty of Medicine and Health minimum requirements are:
- British Council IELTS - score of 7.0 overall, with no element less than 6.5
- TOEFL iBT - overall score of 100 with the listening and reading element no less than 22, writing element no less than 23 and the speaking element no less than 24.
How to apply:
Applications can be made at any time. To apply for this project applicants should complete an online application form and attach the following documentation to support their application.
- a full academic CV
- degree certificate and transcripts of marks
- Evidence that you meet the University's minimum English language requirements (if applicable)
To help us identify that you are applying for this project please ensure you provide the following information on your application form;
- Select PhD in Medicine, Health and Human Disease as your programme of study
- Give the full project title and name the supervisors listed in this advert
Any queries regarding the application process should be directed to firstname.lastname@example.org
1. 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) Plasmacytoid dendritic cells orchestrate innate and adaptive anti-tumor immunity induced by oncolytic coxsackievirus A21. J Immunother Cancer. Jul 1;7(1):164.
2. Virally programmed extracellular vesicles sensitize cancer cells to oncolytic virus and small molecule therapy. 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
3. Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition. 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