Direct identification of the antigenic triggers for immunotoxic T lymphocytes

Applications are invited for a 4 year PhD studentship to join the Thaventhiran lab at the MRC Toxicology Unit, University of Cambridge.

Project Outline:

Immunotherapy toxicity is mediated by the activity of T lymphocyte clones that are driven by specific antigenic targets. In this project the student will use mouse and human samples to identify candidate T cell antigens that drive these maladaptive immune responses.

The project has 3 objectives:

1)   To culture cancer-cell lines (Yumm/Yummer/ Stanger) under defined conditions likely to alter antigen display, including expressing IVTmRNA vaccines, CRISPR knock-out of key epigenetic regulators (HUSH complex), and under situations of cell stress (e.g. ATR inhibition, PARP inhibition). In these cells the student will quantify mRNA, total Protein and eluted pMHC peptidome. To learn rules governing antigen-display, they will compare and contrast the correlation between mRNA, total protein and eluted peptidome for different classes of gene or transcript.

2)   Cancer-cell lines will be implanted into mice and allowed to grow to establish preclinical tumour models. These mice will be treated with either lipid-nanoparticle (LNP) mRNA vaccines or cytotoxic chemotherapy and induced T cell responses tracked using the antigen-receptor signalling reporter mouse. Different tissue sites will be assessed for potentially toxic infiltration of T lymphocytes by histology. The impact of localised sterile inflammation in promoting a toxic T cell infiltration will assessed by administrating carbon tetrachloride (Liver) or dextran sodium sulphate (Gut).

3)   In mice the T cells from tissues will be sorted and immunophenotyped. Antigen-specificity will be assessed by ELISPOT assessment of secreted cytokine following specific candidate peptide stimulation.

These results will determine how changes in transcription caused by immunotherapy can change the display of antigen, and the potential this has for triggering tissue-damaging T cell responses.

The Medical Research Council (MRC) Toxicology Unit is a leading International Research Institute within the School of Biological Sciences, University of Cambridge. The Unit delivers mechanistic toxicology research, pursuing hypothesis-driven toxicological questions with a particular focus on the study of the causal links between exposure to endogenous and exogenous toxicants, molecular initiating events and adverse outcome pathways. The Unit's overall aims are to carry out pioneering research which leads to improved health and to train and mentor the next generation of toxicologists.

The Unit provides a supportive learning environment designed to meet the scientific and transferable skills required for an internationally competitive career. Our PhD Programme aims to train the scientific leaders of the future, giving them rewarding research projects with access to world-class facilities and expertise. Students receive toxicology-specific training in the Unit and through the ITTP | MRC Toxicology Unit (cam.ac.uk)

Application Process

 Applicants should have or shortly expect to obtain a first or good upper second-class degree from a UK university, or an equivalent standard from an overseas university, in a relevant subject. Strong analytical skills, in addition to creativity, curiosity, enthusiasm, and the ability to work in a team are essential.

You are strongly recommended to contact the project supervisor prior to submitting your formal application to find out more about the project and eligibility: Dr James Thaventhiran: [Email Address Removed]

Information regarding the application process can be found at: PhD Programme | MRC Toxicology Unit (cam.ac.uk)

All formal applications will need to be made through the University Application Portal:

PhD in Biological Science (MRC Toxicology Unit) | Postgraduate Admissions (cam.ac.uk)

Your online application must include:

• A CV, including full details of all University course grades to date -

• Contact details for two academic or professional referees

• A personal statement of interest

Closing date: Friday 31st March 2023 or until a suitable candidate is found. Early applications are recommended.