Signaling cross talks between cancer cells and infiltrating tumour monocytes and T cells

Immunotherapy has emerged as the fifth pillar of cancer therapy in addition to surgery, radiotherapy, chemotherapy and targeted therapy. Radiotherapy, chemotherapy and targeted therapy have been developed to selectively kill cancer cells whereas immunotherapy is designed to alter the tumour microenvironment (TME) to enhance immune cells’ ability to kill cancer cells. Immune checkpoint blockade-based combination therapy, immunochemotherapy or immunoradiotherapy, are commonly applied as first line cancer therapy to treat various cancer types including gastrointestinal tumours. A small percentage of cancer patients are cured by the combination therapy whereas a large percentage of patients failed to receive long lasting benefit from the combination therapies. A key challenge in cancer research is to identify the molecular basis for patients heterogenous response to immunochemo- or immunoradio-therapies.

Genetic and non-genetic alterations including epigenetic regulation and target selective transcription of cancer cells define the cancer cell signalling pathways. This cancer cell driven signalling pathway, inside-out signalling pathways, will shape cancer cells’ TME. In return, the behaviour and fate of cancer cells will be influenced by the signalling pathways of their surrounding stromal and immune cells. These TME driven signalling pathways, outside-in signalling pathways, can either be tumour promoting or tumour suppressive. The interactions of the inside-out and outside-in signalling pathways are the key determinants of patients’ response to checkpoint blockade based combination therapy, immunochemo- or imunoradio-therapies.

Through a deep molecular profiling of oesophageal cancer samples derived from a uniquely designed immunochemotherapy trial, Lud2015-005 trial, we made an unexpected finding that high tumour monocytes contents (TMC) in tumours before treatment predict patients’ good overall survival (Carroll et al. Cancer Cell, 2023). This project proposes to study the inside-out and outside-in signalling cross talks between oesophageal cancer cells and immune cells. We will use tumour cells and immune cells derived from operable oesophageal tumours and circulating PBMCs. Focus will be made towards the understanding of how cancer cells can recruit monocytes and under what condition monocytes can enhance the killing property of tumour infiltration CD8 T cells. We will apply cutting edge technologies including but not limited to ex-vivo organoids and 3D printing assisted multicellular co-culture models. Single cell RNA-seq and spatial-transcriptomic analysis will be combined with single cell ATAC-seq and TAPs, technologies that can measure epigenetic alterations such as chromatin remodelling and DNA-methylation. 

Funding Notes

Ludwig studentships provide 4 years funding for a tax-free stipend, currently £21,000 pa and university fees at home and international rates.

Only applications made by the University of Oxford application system for a DPhil in Clinical Medicine will be considered. You may apply for a maximum of two Ludwig projects. Under proposed field and title of research project please enter the project titles in the order of preference. You do not need to provide a research proposal but must include a personal statement.

Please ensure referees are willing to write and submit your reference by the deadline.

Enquiries

Alexandra Royer – alexandra.ward@ludwig.ox.ac.uk – application related enquiries

Applications

https://www.ox.ac.uk/admissions/graduate/courses/dphil-clinical-medicine