Dissecting how TGF impedes the anti-tumour T cell response in CMS4 Colorectal Cancer


   Institute of Immunology and Immunotherapy

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  Dr D Withers, Dr R Drummond  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Additional supervisor Dr Simon Dovedi, AstraZeneca

Informal enquiries are strongly encouraged and should be directed to the project supervisor [Email Address Removed]

Person Specification

A background in immunology or cancer biology is preferable, but not required. Applicants should be intellectually curious and willing to learn, with a drive to conduct research independently. A commitment to research focused on understanding immune responses in vivo is needed. Applicants should hold or realistically expect to obtain at least an Upper Second Class Honours Degree in immunology/biomedical sciences. 

Project details

Overview: This project is an exciting opportunity to train in cancer immunology, and will develop expertise in multiple cutting-edge in vivo approaches1, alongside fundamental research skills. The project sits at the interface of discovery research and translationally-focused efforts to enhance cancer treatments. This is an iCASE studentship with AstraZeneca and will thus benefit from sustained input from leading industrial experts.

Details: We will ask how the tumour microenvironment (TME) of primary and metastatic colorectal cancer (CRC) impedes the T cell response. Within the subsets of CRC that have the worst prognosis, the increased release of the pleiotropic cytokine TGFb orchestrates a suppressive environment that impairs the ability of T cells to effectively kill the cancer2. This PhD studentship is focussed on investigating how TGFb reshapes the interplay of multiple cellular compartments in the tumour, including cancer-associated fibroblasts and both innate and adaptive immune cells. This is required to better design clinical treatments that avoid the toxicity associated with pan-inhibition of this key cytokine and optimally combine with other immunotherapies for robust anti-tumour immunity. The use of in vivo colorectal cancer models that naturally metastasise will facilitate comprehensive testing of different tissue environments and how targeting these, influences the local and systemic anti-tumour immune response. Through using a host of genetically engineered mouse models, we will interrogate precisely which cells are responding to TGFb, why this impedes responding T cells and how best to reinvigorate this critical arm of the anti-tumour response.

The aims of this project are:

1. To define how TGFb inhibition alters the T cell response in primary and metastatic CRC.

2. To test the specific contribution of stromal and immune populations in responding to TGFb and inhibiting the anti-tumour response.

3. To interrogate the TGFb-dependent mechanisms that impede the T cell response in CRC and test immunotherapy combinations designed to enhance the response.

Through addressing these aims, we seek to test our over-arching hypothesis that: Co-ordinated targeting of the inhibitory mechanisms that develop in primary and metastatic CRC will enable immunotherapy-mediated clearance of tumours and establishment of protective immunity.

Experimental methods and research plan: To model human colorectal cancer we will use mouse derived tumour organoids grafted into the colon via a colonoscopy-guided injection3. This model is established in the lab and represents the current gold standard for in vivo colorectal cancer models. Extensive training in this exciting experimental approach will be provided. To unbiasedly investigate the effects of TGFb inhibition, we will use scRNA-seq data from primary and metastatic tumours (generated as part of current grant funding) to initially assess the effects of treatment, utilising established bioinformatics pipelines. The studentship includes the opportunity to learn bioinformatics, specifically scRNA-seq analysis. Flow cytometry and extensive imaging approaches will validate cellular changes at the protein level and capture spatial insight. We will use conditional deletion of Tgfbr2 to block TGFb signalling in specific cell types and interrogate the impact on the T cell response. A key further approach utilised in the project will be the site-specific photo-labelling approaches pioneered by our lab to assess changes in immune cell trafficking, cellular retention in the tumour, and how the primary tumour contributes to the systemic immune compartment. Working with AstraZeneca, we aim to develop tools to manipulate TGFb signalling in specific cell types to better test specific effects in vivo. Finally, we will test tailored immunotherapy combinations informed by experiments outlined above with the aim of modelling better therapy combinations in colorectal cancer.

Expected outcomes and impact: We expect to define the cellular interactions and molecular mechanisms within the TME that respond to TGFb to inhibit the anti-tumour T cell response. Building from this we will devise and test combination strategies tailored to generate robust T cell responses in CRC. The studentship will provide excellent training in a host of key skills and further build experience of interactions in both academic and industrial environments.

Withers Lab: The Withers lab has a long track record in studying immune responses in vivo using creative approaches to unlock new insight. The lab provides a friendly and supportive environment for students developing their research expertise. The lab has a dedicated technician as well as multiple post-doctoral researchers to ensure robust support for PhD students.

How to apply

Click on the institution link which will redirect you to the MRC AIM website which contains full application information and the application forms to complete. Please ensure your application is submitted before the deadline of midday (GMT) Friday 12 January 2024 as late applications will not be considered.

Biological Sciences (4)

Funding Notes

This is a fully funded studentship provided by the Medical Research Council.
If you are successful, you will receive a stipend (currently £18,622 per year for 2023/24) and a tuition fee waiver for 4 years.
Successful candidates will also receive an allowance for a laptop, a travel and conference allowance and an allowance for laboratory/PhD running costs.

References

1. Li, Z. et al. In vivo labeling reveals continuous trafficking of TCF-1+ T cells between tumor and lymphoid tissue. J. Exp. Med. 219, doi:10.1084/jem.20210749 (2022).
2. Tauriello, D. V. F. et al. TGFbeta drives immune evasion in genetically reconstituted colon cancer metastasis. Nature 554, 538-543, doi:10.1038/nature25492 (2018).
3. Jackstadt, R. et al. Epithelial NOTCH Signaling Rewires the Tumor Microenvironment of Colorectal Cancer to Drive Poor-Prognosis Subtypes and Metastasis. Cancer Cell 36, 319-336 e317, doi:10.1016/j.ccell.2019.08.003 (2019).

Where will I study?

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