(Clinical) Protumourigenic inflammation as a determinant and independent immune biomarker of immunotherapy outcome at The University of Manchester on FindAPhD.com

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Dr Santiago Zelenay, Prof Caroline Dive, Dr Elaine Kilgour, Dr Tom Waddell, Dr Manon Pillai No more applications being accepted Competition Funded PhD Project (Students Worldwide)

Manchester United Kingdom Cancer Biology

About the Project

Immunotherapies based on the use of immune check point blockade (ICB) antibodies have transformed the landscape of cancer treatment. However, across malignancies only a fraction of patients derives benefit and predictive biomarkers are lacking. Our recent work combining the use of preclinical cancer models with bioinformatic analysis of patient tumour biopsies has uncovered the value of monitoring protumourigenic inflammation(PTI) to predict patient survival and response to ICB therapy (Bonavita et al.Immunity, 2020). Likewise, we have found that widely-used anti-inflammatory drugs, by targeting immuno suppressive inflammation, represent a promising therapeutic approach to augment the efficacy of ICB (Zelenay et al.Cell, 2015,Pellyand Moeiniet al.Cancer Discovery, 2021).In this project, we will test our working hypotheses that monitoring PTI constitutes an independent immune biomarker of ICB outcome, and that PTI is a major barrier to the efficacy of ICB.

Through deep immune-profiling of in-house cancer patient biopsies, we will investigate the predictive power of measuring PTI alone or in combination with other established bio markers focussing on renal carcinoma - a cancer type in which ICB is the standard of care. We will use our recently-established clinically-compatible protocol to determine the intratumorally inflammatory transcriptional profile of pre-treatment formalin-fixed paraffin-embedded samples from cancer patients that under went ICB.

Further more ,exploiting a pioneering rapid turn around ex vivo tumour fragment platform, we will study the underlying immunobiology of PTI and evaluate the effect of anti-inflammatory drugs for their ability to modulate the tumour microenvironment and fuel anti-cancer T cell-effector function. Lever aging our unique access to patient samples from the MCRC biobank and the complementary breadth of fundamental, translational and clinical immuno-oncology expertise of our team, the over arching goal of this project is to inform the design of better immunotherapy combinations and the development of accurate biomarkers to guide treatment selection

Entry Requirements

Candidates must be post-registration clinicians and ideally have a specialist post in a related subject. It is generally expected that CRTFs will return to a training programme in the UK upon completion of their research degree.

How to Apply

To be considered for this project you MUST submit a formal online application form. Details of how to apply are available here (https://www.bmh.manchester.ac.uk/study/research/funded-programmes/mcrc-training-scheme/apply/). For Visa requirements, international candidates must select the full-time study option.

General enquiries can be directed to [Email Address Removed].

Interviews: Week commencing 10 January 2022

Commencement: April 2022, October 2022 or January 2023

Equality, Diversity and Inclusion

Equality, diversity and inclusion is fundamental to the success of The University of Manchester and is at the heart of all of our activities. The full Equality, diversity and inclusion statement can be found on the website https://www.bmh.manchester.ac.uk/study/research/apply/equality-diversity-inclusion/

Funding Notes

The clinical fellowships are usually tenable for three years. We will provide an appropriate salary in line with the applicant’s current salary and grade, and UK PhD tuition fees. The University of Manchester aims to support the most outstanding applicants from outside the UK. Due to the competitive nature of this scheme, we are only able to offer a limited number of tuition fee scholarships to be awarded to international candidates of exceptional quality.
Funding is available for three years full-time, or pro rata for part-time study. Part-time awards cannot be less than 50% of full time.

References

1. Ribas, A. and Wolchok, J. D. Cancer immunotherapy using checkpoint blockade. Science, doi:10.1126/science.aar4060 (2018).
2. Havel, J. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy, Nature Reviews Cancer , doi: 10.1038/s41568 - 019 -0116 (2019).
3. Litchfield, K. et al. Meta-analysis of tumor - and T cell - intrinsic mechanisms of sensitization to checkpoint inhibition. Cell, doi: 10.1016/j.cell.2021.01.002 (2021).
4.Motzer, R. J.et al. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal - Cell Carcinoma. New England Journal of Medicine , doi: 10.1056/NEJMoa1712126
(2018).
5. Mantovani, A. et al. Cancer - related inflammation. Nature , doi: 10.1038/nature07205 (2008).
6. Shalapour, S. and Karin, M. Pas de Deux: Control of anti - tumour immunity by cancer - associated inflammation. Immunity , doi: 10.1016/j.immuni.2019.06.021 (2019).
7 . Zelenay, S. et al. Cyclooxygenase - dependent tumour growth through evasion of immunity. Cell , doi: 10.1016/j.cell.2015.08.015 (2015).
8. Böttcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer Immune control. Cell , doi: 10.1016/j.cell.2018.01.004 (2018).
9. Bonavita, E. et al. Antagonistic inflammatory phenotypes dictate tumor fate and response to immune checkpoint blockade. Immunity, doi:.10.1016/j.immuni.2020.10.020 (2020)
10. Pelly, V. et al. Anti - inflammatory drugs remodel the tumor immune environment to enhance immune checkpoint blockade efficacy. Cancer Discovery, oi:10.1158/2159-8290.cd -20-1815 (2021).
11. Voabil, P. et al. An ex vivo tumor fragment platform to dissect response to PD -1 blockade in cancer. Nature Medicine , doi: 10.1038/s41591 - 021- 01398 - 3 (2021).
12. Ayers, et al.IFN - γ - related mRNA profile predicts clinical response to PD - 1 blockade. J.Clin .Investig. , doi: 10.1172/JCI91190 (2017)