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How an IFNγ target gene mediates resistance to immunotherapy


Project Description

Metastatic melanoma, a highly aggressive form of skin cancer, can respond well to immunotherapy with immune checkpoint inhibitors, but there are still a significant proportion of patients not benefitting or for whom benefits are not durable. The cytokine IFNγ, while critical for a clinical response to immunotherapy, paradoxically, also reprograms melanoma cells to become resistant. The adaptive resistance program is multifactorial. We have recently identified an actionable IFNγ-induced target contributing to immunotherapy resistance. The PhD project will incorporate in vivo models in immune competent hosts and co-cultures of melanoma and immune cells to further explore the biological roles of this target, while proteomics and in vitro assays will be used to determine its biochemical activity. Through these integrated approaches the student will address the target’s role in immunotherapy resistance.

Through this studentship, the student will acquire practical and theoretical knowledge of tumour transplantation models, co-culture systems, and proteomics, working in an area of significant translational potential, and will be supervised by a multi-disciplinary team.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk.

Funding Notes

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject.

This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor.

References

1. Gide et al. Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Metastatic Melanoma. Clin Cancer Res (2018) 24(6): p. 1260-1270.
2. Ling and Lu. Interferon gamma in cancer immunotherapy. Cancer medicine (2018).
3. Nirschl et al. IFNgamma-dependent tissue-immune homeostasis is co-opted in the tumor microenvironment. Cell (2017) 170:127-141 e115.
4. Benci et al. Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade. Cell (2016) 167(6): 1540–1554.e12.
5. Young et al. An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition. J Exp Med. (2017) 214(6): 1691-1710.

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