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Single-Cell Analysis of γδ T cell Biotherapeutics in Tumour Microenvironment Organoids

  • Full or part time
  • Application Deadline
    Friday, November 29, 2019
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Colorectal cancer (CRC) is a devastating disease that that kills approximately 700,000 people worldwide every year (>16,000 in the UK). While surgery and targeted therapies have improved survival rates for early-stage disease, there is a desperate need for better treatments for late-stage patients.

Chimeric Antigen Receptor (CAR)-T cells and checkpoint inhibitor immunotherapies have revolutionised the treatment of select haematological and solid-cancers respectively. Unfortunately, no immunotherapy options currently exist for CRC. CRC tumours are considered immunologically ‘cold’ and often have a low neo-antigen burden. As a result, cytotoxic T cells struggle to kill CRC cells alone and immune checkpoint release provides little benefit. In contrast, a subset of T cells known as γδ T cells are abundant in intestinal tissue and CRC tumours.

We have recently demonstrated that γδ T cells can be engineered to kill CRC patient-derived organoids (PDOs) via antibody-dependent cellular cytotoxicity (ADCC). This suggests engineered γδ T cells could be a novel biotherapeutic option for CRC patients. Unfortunately, γδ T cells can also be supressed by stromal and myeloid cells in the CRC tumour microenvironment (TME). To utilise γδ T cells as novel anti-CRC biotherapeutics, we must understand how they interact with all cell-types in the CRC TME.

The aim of this project is to explore engineered γδ T cells as novel anti-CRC biotherapeutics using single-cell signalling analysis of γδT-PDO-TME organoids.

Our laboratory has recently developed a novel mass-cytometry (CyTOF) technology to measure single-cell post-translational modification (PTM) signalling in multicellular organoid models of the CRC TME (Qin et al, 2019). This method can measure deep PTM signalling networks across millions of single cancer, stromal, and immune cells from hundreds of different 3D experimental conditions. Using this custom single-cell signalling technology, we will characterise how anti-CEA γδ T cells kill CRC PDOs and to what extent this killing is regulated by stromal fibroblasts and myeloid cells in the TME.

High-dimensional single-cell signalling analysis will be integrated with live-cell multiphoton (in vitro) and intravital (in vivo) imagining to explore spatial interactions between γδ T, CRC, and TME cells. How γδ T cells perform multiple rounds of CRC killing and how non-engineered TME cells can perform ‘bystander’ anti-cancer ADCC will be investigated. By analysing PDO-γδ T cell communication using single-cell proteomics and live-cell imagining, the PhD student will construct a comprehensive cell-cell interaction map of the CRC TME and exploit this knowledge to improve γδ T cell biotherapeutic treatment of solid tumours.

We are looking to recruit an exceptional PhD student – preferably with experience in either organoid culture, T-cell biology, CyTOF, live-cell imaging, and/or single-cell computational biology. The successful candidate will be supported by the Centre’s training programme and have access to multiple training opportunities and world-leading labs across the CRUK City of London Centre.

Potential research placements
1. Live-cell image analysis of γδ T-cell-organoid interactions, supervised by Steven Hooper in Dr Erik Sahai’s laboratory, Francis Crick Institute.

2. Generation of anti-CEA γδ T cells, supervised by Dr John Fisher in Prof John Anderson’s Laboratory, UCL Great Ormond Street Institute of Child Health.

3. Inflammatory inhibition of γδ T cells in the TME supervised by Dr Bea Malacrida & Dr Mina Mincheva in Prof Francis Balkwill laboratory, Barts Cancer Institute.

Funding Notes

Non EU students are not eligible for this funding

References

Qin, X. et al. Single-Cell Signalling Analysis of Heterocellular Organoids. bioRxiv; 2019 DOI: https://doi.org/10.1101/659896

Ege, A.M. et al. Quantitative Analysis Reveals that Actin and Src-Family Kinases Regulate Nuclear YAP1 and Its Export. Cell Systems; 2018, 6(6):692-708.

Fisher J. et al. Engineering γδT Cells Limits Tonic Signaling Associated with Chimeric Antigen Receptors. Science Signaling; 2019, 12(598).

Tape, C.J. et al. Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation, Cell; 2016, 165(4): 910-20.

Tape, C.J. The Heterocellular Emergence of Colorectal Cancer. Trends in Cancer; 2017, 3(2): 79-88.

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