This exciting project will commence in September 2022 and has funding for 3 years. The student will be based primarily at the Barts Cancer Institute, Faculty of Medicine and Dentistry (FMD), Charterhouse Square in the City of London.
This is a Barts Centre for Squamous Cancer - Alexandra Carrell funded PhD studentship.
Background
Although immunotherapy (e.g., immune checkpoint blockade) has shown great promise in the treatment of cancers such as melanoma and Hodgkin lymphoma, the overall response rate is still below 30% for most other cancer types, including squamous cell carcinomas (SCC). Understanding mechanisms of response and resistance will allow the design of rational combinational strategies with immunotherapy. This PhD project will identify tumour-intrinsic changes that mediate and promote immune evasion leading to strategies to overcome immunotherapy resistance in squamous cancers.
Hypothesis
Functional genomic alternations acquired by squamous cancer cells act in a coordinated manner to regulate immune signalling, which can increase the sensitivity or resistance of squamous cancer cells to immune cell mediated toxicity. Across the many different tissue sites of SCC development including skin, oesophagus and oral cavity, we propose there are shared SCC tumour-intrinsic characteristics and immune evasion mechanisms to design pan-SCC therapies, as well as those specific to the SCC sites.
Aims
- Systematic investigation of immune landscape and genomic correlates in SCCs. We will use our previously generated matched whole-exome sequencing (WES) and RNAseq data for cutaneous (n=400) and oesophageal (n=120) SCCs. We will incorporate TCGA matched WES and RNA-seq for lung (n=504), head and neck (H&N, n=527), cervical (n=255) and oesophageal (n=90) SCCs. Deliverable: the full catalogue of immune heterogeneity and their genomic correlates across SCCs.
- Integration with genome-wide CRISPR screens and assess their response to immune-mediated killing. We will integrate recently published genome-scale screens of tumour cell lines cultured with immune cells and/or growing in vivo treated with immunotherapy, and identify candidate genes (from Aim 1) that affect cancer cell fitness under T or NK cell killing pressure or treated with immunotherapy. Deliverable: identification of functionally important genes/modules associated with immune mediated killing or resistance across SCCs.
- Functional validation of genetic alterations that mediate immune sensitisation or evasion. We will validate our findings of immune estimates and their genomic correlates in SCC cell lines using a range of functional genomics techniques. Deliverable: confirmation of genomic alterations / genetic circuits involved in immune evasion of SCCs.
This multidisciplinary project will expand our knowledge of tumour-intrinsic mechanisms of immune response and evasion across SCCs, providing pan-SCC targets for combination strategies with immunotherapy.
Student training
Student will be trained with cutting-edge bioinformatics, data analytics, immunogenomics and functional genomics techniques, including genome-wide CRISPR screens, CRISPR-Cas9 gene knockout and RNA-seq. These are all highly desirable in their future career.
Academic Entry Requirements
All applicants should have or be expecting:
- A first or upper second class honours degree in a relevant biological subject from a UK university or the international equivalent from a recognised institution. For international equivalencies please see Queen Mary International Office. Or;
- A medical degree from a recognised institution.
English Language Requirements
Applicants for whom English is not a first language will also require a minimum IELTS score of 6.5 (with 6.0 in the written component) or equivalent, unless your undergraduate degree was studied in, and awarded by, an English speaking country. For more information on acceptable English language qualifications please see here.
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