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Defining targets modulating anti-tumour immune effectors in vivo

  • Full or part time
  • Application Deadline
    Friday, January 11, 2019
  • Funded PhD Project (Students Worldwide)
    Funded PhD Project (Students Worldwide)

About This PhD Project

Project Description

The Cancer Research UK Beatson Institute in Glasgow is one of the world-leading centres for cancer research. The Institute provides an outstanding research environment, underpinned by state-of-the-art core services and advanced technologies with special emphasis on imaging, metabolomics and in vivo models of cancer.

Immunotherapy has shown dramatic results in recent years, inducing strong and durable clinical responses in many cancers that have previously been associated with poor outcomes. Checkpoint blockade therapy in particular has shown promising results, producing long-term clinical responses in patients who did not respond to standard therapies. While checkpoint blockade therapies are approved for use in a number of different indications, the dramatic results outlined only apply to a subset of patients. Furthermore, some cancer types such as pancreatic, colorectal and prostate cancers rarely benefit from checkpoint blockade. Some resistant tumours can be rendered susceptible to checkpoint blockade by addition of therapeutic vaccination and tumour infiltrating lymphocyte (TIL) therapy - where tumour-specific T cells present in the tumour are isolated and expanded ex vivo before being reintroduced into the patient - leading to tumour regression. This, along with the observation that better CD8 T cell infiltration is associated with sensitivity to checkpoint blockade, suggests that improving the breadth and character of T cell priming to generate more effective anti-tumour effectors could synergise with current immunotherapy approaches to expand their benefits to more patients.

T cell priming occurs in the lymph node (LN), an organised, dynamic environment inhabited by a diverse population of cells that coordinate appropriate and proportionate immune responses. The LN, however, is anatomically distal to the site of peripheral tissue challenge and so must garner information from secondary sources such as soluble factors, extracellular vesicles and migratory cells; cells residing in the LN, such as stroma and LN resident dendritic cells (resDC), then interpret these signals and coordinate an appropriate response. Migratory dendritic cells (MigDC) in particular have been shown to induce stromal remodelling and, using a novel method of tracking tumour antigens, we have recently shown that they also bring antigen to the lymph node and disseminate this to cells within the tumour-draining LN microenvironment. MigDC too have been suggested to be the critical partners stimulating anti-tumour CD4 and CD8 T cells through the use of in vitro T cell stimulation assays (1,2).

We have, however, recently found that antigen-loaded resDC too can stimulate anti-tumour T cells and induce a different T cell differentiation state than do migDC. The role of these resDC is very poorly understood and in the tumour setting is almost entirely opaque. This is in part due to the lack of genetic models allowing in vivo manipulation of DC subsets due to the similarities between migratory and resident populations. Interestingly, however, these migratory and resident DC subsets develop in their tissue of interest after progenitors, pre-DC, migrate to the tissue or LN and differentiate in situ (3). This project aims to optimise and apply an in vivo screen to determine how pre-DC migration into tissues is regulated, allowing us to block pre-DC ingress and thereby eliminate resDC populations or modulate tumour DC levels in vivo. Similar approaches have previously been used to identify key factors in tumour T cells (4). Using this screen we can elucidate the functional roles of resDC populations for the first time in vivo, and by applying the findings within the tumour microenvironment we would then be able to rationally determine approaches to improve pre-DC ingress, increasing the number of stimulatory DC that has been shown to correlate with improved clinical outcomes (5,6).

Specific objectives
- Optimise existing strategies to differentiate and transduce pre-DC in vitro from mouse bone marrow (7)
- Develop a pooled CRISPR library targeting candidate genes involved in migration and localisation
- Screen knockouts for their ability to enter LN or tumours
- Validate hits using mouse models

Techniques
- Molecular biology
- Multicolour flow cytometry
- CRISPR gene editing
- In vitro bone marrow cultures
- Use of mouse models and generation of bone marrow chimeras
- Advanced imaging including confocal microscopy and intravital imaging

To apply, please click on the ’Apply Online’ button, which will take you to the Beatson Institute website where you should fill in the application form. Please do not email your CV.

References

1. Roberts, E. W. et al. Critical Role for CD103+/CD141+ Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma. Cancer Cell 30, 324–336 (2016).

2. Salmon, H. et al. Expansion and Activation of CD103+ Dendritic Cell Progenitors at the Tumor Site Enhances Tumor Responses to Therapeutic PD-L1 and BRAF Inhibition. Immunity 44, 924–938 (2016).

3. Liu, K. et al. In vivo analysis of dendritic cell development and homeostasis. Science 324, 392–397 (2009).

4. Zhou, P. et al. In vivo Discovery of Immunotherapy Targets in the Tumor Microenvironment. Nature 506, 52–57 (2014).

5. Barry, K. C. et al. A natural killer-dendritic cell axis defines checkpoint therapy-responsive tumor microenvironments. Nat. Med. 24, 1178–1191 (2018).

6. Broz, M. L. et al. Dissecting the tumor myeloid compartment reveals rare activating antigen-presenting cells critical for T cell immunity. Cancer Cell 26, 638–652 (2014).

7. Schlitzer, A. et al. Identification of cDC1- and cDC2-committed DC progenitors reveals early lineage priming at the common DC progenitor stage in the bone marrow. Nature Immunology 16, 718–728 (2015).

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