Impact of mutant immune infiltrates on response to cancer immunotherapy

Primary supervisor: Francesca Ciccarelli, Queen Mary University of London

Secondary supervisor: Dominique Bonnet, Francis Crick Institute

Project

Background and project description: Clonal haematopoiesis of indeterminate potential (CHIP) is a common age-related condition in which blood-forming stem cells acquire mutations with a competitive advantage. These mutant cells generate populations of circulating immune cells that are associated with an increased risk of blood cancers, cardiovascular disease and adverse outcomes in solid tumours. However, we still know little about how CHIP-mutant immune cells interact with cancer cells or influence responses to treatment. This four-year PhD project brings together two recently established areas of research in our two laboratories:

The Ciccarelli laboratory investigates the mechanisms driving cancer evolution. Using spatial transcriptomics, cell co-cultures and systems-biology, we recently showed that colorectal cancer (CRC) patients can be stratified according to the spatial organisation and relative abundance of cancer and immune cells within the tumour microenvironment [1,2]. Importantly tumours enriched for intraepithelial cytotoxic lymphocytes and pro-inflammatory macrophages respond significantly better to immunotherapy. Building on these findings, we have begun to resolve the molecular communication among cancer cells, lymphocytes and macrophages at single-cell resolution. Our unpublished results indicate that spatial proximity between these populations induces reciprocal changes in cell state that could potentially be targeted to improve therapeutic response.

The Bonnet laboratory has longstanding expertise in the mechanisms regulating human haematopoiesis in health and disease. Using CRISPR-edited human cells and humanised mouse models, we recently showed that human hematopoietic stem cells with mutations in the TET2 gene are refractory to inflammatory stimuli whereas their progeny (in particular monocytes and macrophages) are hyperinflammatory, further supporting the clonal selection of the TET2^mut clones [3]. These findings are particularly relevant because TET2 is one of the genes most frequently mutated in CHIP, which becomes increasingly common with age and may alter the immune environment of solid tumours [4].

By combining the complementary expertise of the two laboratories, this project will investigate how immune cells carrying common CHIP-associated mutations interact with colorectal cancer cells and whether these altered interactions influence the response to immunotherapy in the context of not of inflammatory stimuli. The project will focus on lymphocytes and macrophages because their abundance, functional state and spatial relationship with CRC cells are strongly associated with treatment response. The project has three aims:

1. Generate lymphocytes and macrophages carrying common CHIP-associated mutations from human haematopoietic stem and progenitor cells.

2. Co-culture mutant immune cells with patient-derived CRC organoids and use functional, molecular and single-cell approaches to determine how CHIP mutations affect the states and activities of both cancer and immune cells, compared with their wild-type counterparts in the context or not of inflammatory stimuli.

3. Determine whether the cellular and molecular changes observed in co-culture are traceable in human CRC samples, and test whether these interactions can be therapeutically modulated using patient-derived tumour fragments.

Candidate background

The project will provide training at the interface of immunology, cancer, stem-cell and computational biology, suiting candidates with a strong background in human biology and an interest in understanding how interactions between cancer and immune cells influence treatment response. Previous experience in cell or molecular biology (mammalian cell culture, flow cytometry, genome editing or organoid models) is essential.

Potential Research Placements

1. Jo Spencer, School of Immunology & Microbial Sciences, King’s College London
2. Chris Tape, Cancer Institute, UCL
3. CoL Centre Organoid Facility, UCL

References

1. Bortolomeazzi, M., Keddar, M.R., Montorsi, L., … Ciccarelli, F.D. (2021). Immunogenomics of Colorectal Cancer Response to Checkpoint Blockade: Analysis of the KEYNOTE 177 Trial and Validation Cohorts. Gastroenterology 161, 1179-1193. 10.1053/j.gastro.2021.06.064.
2. Acha-Sagredo, A., Andrei, P., Clayton, K., … Ciccarelli, F.D. (2025). A constitutive interferon-high immunophenotype defines response to immunotherapy in colorectal cancer. Cancer Cell 43, 292-307.e297. 10.1016/j.ccell.2024.12.008.
3. Huerga Encabo, H., … Bonnet D. (2026). Human TET2-Mutant Clonal Hematopoiesis Expansion Is Driven by Distinct Inflammatory Signaling Responses in Stem Cells Versus Myeloid Progeny. Blood Cancer Discovery 7, 287-305. 10.1158/2643-3230.Bcd-25-0070.
4. Nguyen, Y.T.M., … Sakata-Yanagimoto, M. (2025). Clonal Hematopoiesis and Solid Cancers. Cancer Science 116, 2055-2063. https://doi.org/10.1111/cas.70097.