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Radiation induced oxidative DNA damage and cancer immunology in NSCLC


Project Description

Forty percent of all patients cured of cancer have radiotherapy as part of their treatment. Lung cancer is the most common cause of cancer death in the UK and in non-small cell lung cancer (NSCLC) radiotherapy is the standard of care for patients with stage III disease. However, only 15% of patients with stage III NSCLC are alive 5 years after treatment. Radiotherapy is most commonly delivered using photons but can be delivered using other ionising particles such as protons or carbon ions. Most DNA damage from ionizing radiation (IR) occurs indirectly from radiolysed water resulting in oxidative damage as opposed to single or double strand breaks. How radiation dose and type impact the quantity and genomic distribution of this damage remains poorly defined. IR induced DNA damage can result in senescence occurring in tandem with the production of a myriad of immunosuppressive (IL-6, IL-10) or immunostimulatory (CXCL1, CCL2) cytokines in what is termed the senescence-associated secretory phenotype (SASP) [1]. The immunological effect of IR has significant translational potential given the possibility of combining radiation with immunotherapy in the clinic. Genetic modification of APE1 and OGG1 which are involved in the repair of apurinic/apyrimidinic and oxoguanine residues respectively has been shown to have immunological effects linking the oxidative damage induced by radiation with the SASP [2].

The major objectives of this project are to:
1. Use next generation sequencing (NGS) methods to quantify the impact of radiation dose and particle type (photons vs protons) on the quantity and genomic distribution of oxidative damage in lung cancer. The AP-seq method, developed at the Francis Crick Institute, is capable of mapping apurinic sites and 8-oxo-7,8-dihydroguanine bases at approximately 250-bp resolution on a genome-wide scale and will be used as the basis of this project [3].
2. Link the quantity and genomic distribution of IR induced genomic damage with the SASP. CRISPR/Cas9 will be used to assess the impact of driver mutations effecting oxidative damage repair on IR induced oxidative damage and the subsequent immunosuppressive versus immunostimulatory balance of the SASP.
3. Natural Killer (NK) cells play a significant role in the removal of senescent tumour cells [4]. The optimal way to combine NK cell targeted immunotherapy in combination with IR to augment an anti-tumour immune response with a view to clinical translation will be investigated.

The ideal candidate will be motivated to develop an expertise in NGS methods and computational analysis of DNA damage with a willingness to embrace both wet and dry lab skills. The candidate will ideally have a background in biochemistry, biology, immunology and/or data science and will be supported through the training programme to develop the requisite skill set required to complete this project.


Potential research placements

1. Immune Regulation and Tumour Immunotherapy Research Group, UCL (Prof Sergio Quezada). To understand basics of cancer immunology, learn co-culture methodology to with NK cells and develop a network of colleagues working in cancer immunology.

2. DSB Repair Metabolism Laboratory, The Francis Crick Institute. (Prof Simon Boulton). To learn about assays to quantify DNA damage response and genetically engineered models to manipulate DNA damage repair pathways.

3. Bill Lyons Informatics Centre, UCL Cancer Institute. To develop bioinformatics skills and develop a network of colleagues working in genomics analysis.

Funding Notes

Only EU / UK students are eligible to apply

References

1. Faget, D.V. et al. Unmasking senescence: context-dependent effects of SASP in cancer. Nat Rev Cancer;2019 Aug;19(8):439-453.

2. Nakad, R and Schumacher B. DNA Damage Response and Immune Defense: Links and Mechanisms. Front Genet; 2016 Aug 9;7:147.

3. Poetsch, A.R. et al. Genomic landscape of oxidative DNA damage and repair reveals regioselective protection from mutagenesis. Genome Biol; 2018 Dec 7;19(1):215

4. Ruscetti, M et al. NK cell-mediated cytotoxicity contributes to tumor control by a cytostatic drug combination. Science; 2018 Dec 21;362(6421):1416-1422.

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