Objective
T cell dysfunction is a key problem in cancer, enabling not only tumorigenesis but also causing resistance to immunotherapy. Induction of immune checkpoints is a hallmark of T cell dysfunction, but clinical blockade by PD-1 and CTLA-4 antibodies solves this problem for few patients only. Dysfunction is driven also by additional mechanisms, including chronic stimulation and metabolic insufficiency. A better mechanistic understanding will be imperative for improving immunotherapy. My laboratory recently launched ReverT, a genome-wide CRISPR-Cas9 screening program to identify genes, ablation of which reverses dysfunction in primary T cells. To de-risk this application, we have already successfully completed three such screens in vitro, for chronic antigen stimulation, metabolic stress and PD-1 induction, validating and characterizing several dysfunction genes not previously reported. Furthermore, an independent follow-up re-screen with a Dysfunction Reversion Candidate (DRC) mini-library containing the top 100 hits of each of these screens validated >100 genes that reversed T cell dysfunction in vitro. Here, we will carry out the most challenging and important step: to systematically validate and mechanistically characterize this collection of T cell dysfunction genes in vivo. This will be done in a pooled and multimodal fashion, analyzing multiple dysfunction phenotypes in parallel, specifically immune checkpoints, exhaustion, metabolism, recruitment and proliferation. Our proof-of-concept results indicate that the DRC library contains nodal factors, operating in several seemingly different dysfunction settings, which may thus in fact be linked. We will use a collection of adoptive cell transfer mouse and human tumor models for validation and mechanistic characterization, as well as primary human T cells in patient-derived tumor fragments. Lastly, we will translate our findings to a preclinical setting, aiming to achieve more durable clinical responses.
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.
- medical and health sciences clinical medicine oncology
- medical and health sciences basic medicine immunology immunotherapy
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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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HORIZON.1.1 - European Research Council (ERC)
MAIN PROGRAMME
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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.
HORIZON-ERC - HORIZON ERC Grants
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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) ERC-2021-ADG
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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.
1066 CX AMSTERDAM
Netherlands
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.