Breaking down DNA repair: Understanding how DNA mismatch repair loss provokes distinct cancer immune-phenotypes and treatment outcomes
Primary supervisor: Sarah Martin, Queen Mary University of London
Secondary supervisor: Marnix Jansen, UCL
Project
The Problem:
MMR deficiency is due to loss of one of the 4 MMR genes (MLH1, MSH2, MSH6 and PMS2), occurs in ~20% of all cancers, and results in a hypermutator phenotype. Treatment of patients with mismatch repair deficient (MMRd) cancers has been revolutionised with the introduction of immune checkpoint inhibitors (ICIs) [1,2]. However, whilst some MMRd patients show dramatic responses, about half of all patients with advanced disease fail to respond. The reasons for these dramatically different treatment outcomes remain unclear. Our labs have previously shown that different synthetic lethal interactions exist depending on the specific MMR gene loss [3,4] (Martin group) and that immune selection drives adaptive mutability of MMRd tumours by provoking compound MSH6 mutations [5] (Jansen group). Together our results provide compelling data to suggest that distinct neoantigen-immune phenotypes depending on specific MMR gene involved may drive treatment response and clinical outcomes.
The Project:
In this PhD project, we aim to understand how cancer-immune interactions are shaped by specific MMR gene loss, drive neoantigen evolution and how this may influence treatment response. This will allow clinical management of patients to be tailored to specific MMR defect, whilst balancing expected treatment response and immune toxicities.
Aim 1: Determine the influence of specific MMR gene loss on response to immune checkpoint blockade Using a panel of murine colorectal cancer (CRC) MMRd (MLH1, MSH2, MSH6, PMS2) knockout cell lines, we will perform syngeneic experiments in immuno-competent Balb/c to investigate how specific MMR loss shapes the immune contexture and tumour-immune cell interaction. This analysis will allow us to understand how different MMR gene loss influences ICB response and immune micro-environment.
Aim 2: Identify gene expression patterns upon specific MMR gene loss underpinning treatment response Leveraging the data from Aim 1, here we will carry out single-cell RNA sequencing on cells isolated from MLH1, MSH2, MSH6 and PMS2-deficient CRC primary tumours to determine the functional consequences of specific MMR gene loss and clinical ICB response. Mechanistic assays will be performed based on differentially expressed genes identified to determine their influence on immune cell killing.
Aim 3: Understand how specific MMR gene loss provokes distinct cancer immune-phenotypes Here we will perform multiplex IHC labelling of key immune cell populations on MLH1, MSH2, MSH6 and PMS2-deficient CRC primary tumours. This analysis will enable us to quantify immune cell infiltration across the different MMR genotypes.
Candidate background
The project would suit a cancer evolution and genome stability enthusiast from any basic science background. We are particularly looking for a talented candidate who shares our enthusiasm for evolutionary cancer genetics and who is keen to develop clinically-informed quantitative models for clinical patient benefit, and a strong drive to develop a career in academic translational cancer research. Previous experience in evolutionary cancer research or quantitative immune-oncology is welcomed, but a strong drive to pursue a interdisciplinary scientific career is equally important. The studentship will provide advanced training in cutting edge next generation sequencing pipelines, together with the necessary high dimensional data analysis context to analyse this data.
Potential Research Placements
- Jane Sosabowski, Barts Cancer Institute, Queen Mary University of London
- Marnix Jansen, UCL Cancer Institute
- Kai-Keen Shiu, University College London Hospital
References
- Andre et al. The New England journal of medicine 2020; 383:2207?2218
- Lenz et al. Journal of Clinical Oncology 2020; 38:4040?4040.
- Martin et al. Cancer Cell. 2010; 17(3): 235-248.
- Martin et al. EMBO Mol. Med. 2009; 1(6-7): 323-337.
- Kayhanian et al. bioRxiv 2022.03.06.482973