2023 PhD Project Ciccarelli2022-10-07T15:05:01+00:00

Role of tumour suppressor-induced immune escape in the early phases of cancer evolution

Primary supervisor: Francesca Ciccarelli, King’s College London

Secondary supervisor: Ilaria Malanchi, Francis Crick Institute

Project

The immune system acts as a protection barrier against tumour formation and restoring its capability to eradicate malignant cells is at the core of cancer immunotherapy. Despite this, tumours can evade immune control and immunotherapy is not always effective, suggesting that the crosstalk between cancer and the immune system is complex. Several independent lines of evidence (some of which from our own labs) point towards a role of tumour suppressor genes (TSGs) (1) in early immune evasion. For example, healthy human tissues start to accumulate somatic alterations in TSGs well before cancer transformation (2). These mutations often target stem/progenitor cells, which are the most likely cells of origin of epithelial cancers, for example Lgr5+ cells in gastrointestinal cancer (3,4). Finally, TSGs are preferentially inactivated in the presence of an intact adaptive immune system (5). These observations lead us to hypothesise that TSGs acquire non-immunogenic loss-of-function alterations very early in the tumorigenic process resulting in their inactivation. This, in turn, initiates a cascade of events eventually culminating in immune escape.

This project aims to test this hypothesis and investigate the initial phases of cancer-immune system interaction, namely when and how TSG alterations in pre-tumour cells lead to elude the immune system control and promote cancer initiation. The outcomes of this project will advance our understanding of tumour initiation by elucidating how genetic alterations occurring in the cancer cells cause immune evasion. This will ultimately enhance cancer early detection and extend the impact of immunotherapy by understanding the starting phases of cancer evolution.

The project will focus on gastrointestinal cancers and will be divided in four aims:

Aim 1: Analyse somatic mutation and gene expression data from healthy human tissues to somatic identify loss-of-function mutations altering TSGs and quantify their immunogenicity
Aim 2: Knock-out selected TSGs from Aim 1 specifically targeting cancer cells of origin (Lgr5+ cells) in mouse models to reproduce clonal expansion observed in human
Aim 3: Expose TSG-mutant mice to chronic inflammation or chemical carcinogenesis to initiate tumourigenesis.

Functional changes in mutant (Aim 2) or transformed (Aim 3) epithelial cells and surrounding immune cells will be quantified through single-cell RNAseq and imaging mass cytometry.

Aim 4: Verify the presence of cell populations or molecular markers from Aim 3 in human early dysplastic lesions through immunostaining, spatial transcriptomics, and imaging mass cytometry.

Candidate background

This project is highly interdisciplinary as it combines computational analyses of cancer genomics, spatial transcriptomics, and high-dimensional imaging data with mechanistic studies in mouse and final validation in human clinical samples.

The project is suited for a student with a quantitative biology background (statistics, computation, data analytics) who wants to gain new skills in wet-lab biology or vice-versa.

Potential Research Placements

  1. Ben Werner, Barts Cancer Institute, Queen Mary University of London
  2. Benny Chain, Computational Immunology Lab, UCL
  3. Gitta Stockinger, AhRimmunity Lab, Francis Crick Institute
  4. Manuel Rodriguez-Justo, Human Pathology Lab, UCLH

References

  1. Dressler L, Bortolomeazzi M, Keddar MR […] Ciccarelli FD Comparative assessment of genes driving cancer and somatic evolution in non-cancer tissues: an update of the Network of Cancer Genes (NCG) resource. Genome Biology 2022; 23 (1): 35.
  2. Acha-Sagredo A, Ganguli P, Ciccarelli FD. Somatic variation in normal tissues: friend or foe of cancer early detection? Preprints 2022: doi: 10.20944/preprints202207.200321.v202201.
  3. Barker N, Ridgway RA, van Es JH et al. Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 2009; 457 (7229): 608-611.
  4. van Neerven SM, de Groot NE, Nijman LE et al. Apc-mutant cells act as supercompetitors in intestinal tumour initiation. Nature 2021; 594 (7863): 436-441.
  5. Martin TD, Patel RS, Cook DR et al. The adaptive immune system is a major driver of selection for tumor suppressor gene inactivation. Science 2021; 373 (6561): 1327-1335.
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