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Defining molecular mechanisms for modulation of T cell function by tumour derived extracellular vesicles


   Cardiff School of Medicine

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  Dr S Man, Prof Aled Clayton  No more applications being accepted  Self-Funded PhD Students Only

About the Project

Immunotherapy based on the activation of tumour specific cytotoxic T cells has shown promise for the treatment of haematological malignancies. However, this approach has generally not been effective for treatment of solid cancers. This is thought, in part to be a consequence of the tumour microenvironment which suppresses the activation of T cells in cancer tissue. The tissue-mechanisms responsible for immune suppression are complex, and extensive work by us and other researchers have demonstrated multiple, potent roles for extracellular vesicles (EV), that down-regulate several receptors on T cells that are critical for their anti-tumour functions. Tumour derived EV contain a cargo of molecules capable of mediating functional changes in T cells, including many classes of RNA. However, it is not clear whether EV can mediate their effects by transferring RNA to transcriptionally reprogram T cells. One report hints that tumour antigens become expressed by T cells, mediated by transfer of EV from cancer cells to T cells- but the impact and relevance of this is currently unclear. This project will study the interaction of tumour derived extracellular vesicles (EV) with tumour specific CD8+ T cells and has 3 main components:

1.         Visualisation of intracellular entry and trafficking of tumour derived EV in T cells.Our laboratory has recently developed novel tumour cell lines that secrete fluorescently labelled EV. These will be co-cultured with CD8+ T cells and analysed with flow cytometry and high resolution microscopy. A combination of imaging and pharmacological inhibitors will be used to define the routes and kinetics of EV cell entry and their intracellular fate. The impact of T cell activation status and phenotype (CD4/CD8) on EV entry and trafficking will also be determined.

2.         Demonstration of transcriptional reprogramming of T cells. The delivery of EV-RNA cargo into T cells, and the resultant alterations in the T cell transcriptome will be explored. Bioinformatic analysis will focus on tumour associated antigens and functionally important T cell machineries such as check-point inhibitors.

3.         Impact of EVs on the function of T cells. Well-established T cell assays will be used to measure the impact of EVs on the effector function of T cells. Tumour derived EV will be compared to EV from normal cells for their capacity to modulate the function of T cells. A repertoire of functional assays will be used to measure changes in cytokine secretion, cytotoxity and proliferation.

This project will provide the most comprehensive analysis of tumour derived EV interactions with T cells to date, providing novel insights into the entry of EVs and the functional impact of EV cargo delivery. The overall aim of the project is to understand the molecular mechanisms for suppression of T cell activity by the tumour microenvironment. Circumventing these mechanisms may improve prospects for immunotherapy of cancer.

Application Process

We are seeking enthusiastic and motivated students with an interest in Cancer or genomic research. Applicants should possess a minimum of an upper second-class Honours degree, master's degree, or equivalent in a relevant subject.

Applicants whose first language is not English are normally expected to meet the minimum University requirements (e.g. 6.5 IELTS)

The total duration of this PhD programme is 3.5 years. Following discussion with proposed supervisors and to be considered you must submit a formal application via Cardiff University’s online application service. Medicine - Study - Cardiff University

There is a box at the top right of the page labelled ‘Apply’, please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (i.e. October 2022). This will take you to the application portal.

In the ‘Research Proposal’ section of the application enter the name of the project you are applying to.

Candidates must submit the following information:

  • Supporting statement 
  • CV 
  • Qualification certificates 
  • Proof of Funding i.e. a letter of intent from your sponsor or confirmation of self-funded status.
  • References x 2 
  • Proof of English language (if applicable)

Closing date for applicants is 31st March 2022.


Funding Notes

This is a Self-Funded/Sponsored PhD opportunity.
FUNDING REQUIRED:
Full UK/EU or International Tuition Fees
UK Living Expenses
Bench Fees (where applicable)
Open to all students of any nationality without restrictions (UK/EU and International)
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