Radiation drug combinations to improve immune response in metastatic colorectal cancer
Primary supervisor: Maria Hawkins, UCL
Secondary supervisor: Marco Gerlinger, Queen Mary University of London
Project
Project background and description:
Survival in mismatch-repair proficient (MMRp) metastatic colorectal cancer (mCRC) remains poor and systemic therapy is the mainstay of treatment. Immunotherapy with immune checkpoint inhibitors (ICIs) has changed the way many types of metastatic cancer are treated in the clinic but MMRp mCRC have proved highly resistant to ICIs. Colon cancer metastases commonly show an immune cell excluded or immune desert phenotype. The lack of T-cell infiltration likely explains poor ICI response and represents a major challenge for more effective treatment. Combining ICIs with radiation can augment immune response and promote T-cell infiltration into tumours. However, but mechanisms are poorly understood and which type of radiation (e.g. X-rays or particle therapy) is most effective for this remains unknown.
The aim of this project is to explore the specific mechanisms through which distinct types or RT (X-rays vs protons) impact the efficacy of ICI in patient derived CRC organoids (PDOs) that were established from liver metastases. We will co-culture these PDOs with fibroblasts, hepatocytes and allogeneic and autologous peripheral blood lymphocytes to model immune responses in vitro. We will then explore how different radiation types impact immune cell migration, infiltration into PDOs and immune cell activation. Mechanistic studies will shed light onto the molecular pathways that regulate these immune responses. These insights should furthermore inform how the response can be augmented.
Aims:
- Establish the PDO and T-cell co-culture systems
- Quantify changes in immune cell migration, infiltration and activation/signalling after proton and X-ray radiation
- Use single cell sequencing to define what mechanisms get activated in cancer cells and T-cells by different types of radiation.
- Manipulate promising signalling pathways identified in 3) with drugs to further enhance responses.
Candidate background
This project is suited to a candidate with a strong interest in cancer biology and experience in cell culture. Experience in PDO culture, radiation delivery and/or single-cell analysis would be useful.
Potential Research Placements
- Chris Tape, UCL Cancer Institute
- Fran Balkwill, Barts Cancer Institute, Queen Mary University of London
- Simone Zaccharia, UCL Cancer Institute
References
- Sufi & Qin et al., Nature Protocols, 2021.
- Cataneo et al., Nature Protocols, 2019.
- Tiriac et al., Cancer Discovery, 2018.
- Isella et al., Nature Genetics, 2015.