Project description
A holistic view on cancer immune evasion
Understanding anti-tumour immunity is central for the design of effective immunotherapy strategies. However, the clonal nature of tumours leads to heterogeneity in treatment response and even drug resistance. Scientists of the EU-funded TxImmuneOrganoids project propose to address this challenge through the development of appropriate patient-derived models. They will establish organoids from non-small cell lung cancer (NSCLC) patients and study their interaction with autologous or allogeneic T cells. Results will provide a holistic and mechanistic overview of immune surveillance and evasion in NSCLC. Moreover, identification of putative molecular determinants may open opportunities for novel anti-cancer interventions.
Objective
Immune checkpoint blockade (ICB) has revolutionised treatment of patients with non-small cell lung cancer (NSCLC), but is effective in only ~20% of patients. Anti-tumour immunity is highly heterogeneous within tumours, and intra-tumour heterogeneity (ITH) is a major driver for treatment resistance. However, the mechanistic basis of intra-tumour immune heterogeneity (ITIH) is unclear, largely due to the absence of appropriate functional models.
Here, I aim to identify the genetic or transcriptomic drivers of ITIH, and their impact on immune surveillance and control. I have recently developed an organoid – T-cell co-culture system that I will use to generate personalised models of ITIH. Leveraging the TRACERx lung cancer evolution study, I will establish multiple clonal organoid lines from the same tumour from NSCLC multi-region biopsies. Each organoid subline will be co-cultured with autologous T-cells to evaluate how they differ in sensitivity to T-cells. For each patient, the 6 most sensitive and 6 most resistant sublines will be used for DNA and RNA sequencing to identify mutations (including neo-antigens), copy number alterations and differentially expressed genes associated with resistance to T-cells. Candidate subclonal immune evasion factors will be validated in organoids by CRISPR-Cas9. I will prioritise genes by cross-referencing with genes associated with immune-cold regions in the TRACERx cohort. I will also perform pooled enrichment screens as a less biased approach.
The integration of novel organoid technology with ‘big data’ from TRACERx allows moving beyond merely descriptive studies of ITIH. This will result in the most fine-grained mechanistic study of ITIH to date.
Fields of science (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- natural sciences biological sciences genetics DNA
- medical and health sciences clinical medicine oncology lung cancer
- natural sciences computer and information sciences data science big data
- natural sciences biological sciences genetics mutation
- natural sciences biological sciences genetics RNA
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Keywords
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2020
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
NW1 1AT London
United Kingdom
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.