Objective
Resistance of cancers to immune checkpoint blockade (ICB) can result from a deviated taxonomic composition of the intestinal microbiota. A surge in the Enterocloster genus, for instance following discontinuation of antibiotics or chronic inflammation caused by tumors, induces the downregulation of MAdCAM-1 in the ileal lamina propria and mesenteric lymph nodes through perturbations of biliary salts. In turn, the ileal MAdCAM-1 loss induces the exodus of immunosuppressive T lymphocytes expressing the MAdCAM-1 receptor α4β7, i.e. FoxP3+ RAR-related orphan receptor gamma t (RORγt+) regulatory (Tr17) cells, from the gut to distant tumors. Disruption of the MAdCAM-1–α4β7 axis compromises the efficacy of immunotherapy and reprograms the tumor microenvironment towards a regulatory phenotype. Moreover, serum soluble MAdCAM-1 is a proxy of intestinal dysbiosis and a robust predictor of survival in cancer patients treated with ICB. To decipher the biological significance of these findings, we will first investigate the transcriptional and post-translational mechanisms regulating MAdCAM-1 expression and function (Task 1), in particular neuroendocrine and metabolic cues. Next, a comprehensive phenotyping of the emigrating enterotropic T cells reaching the tumor by single cell transcriptomics and genomics, as well as specific genetic and immunopharmacological intervention on T lymphocytes and cancer cells will lead to the identification of the molecular mechanisms regulating the gut-tumor axis (Task 2). We will investigate how enterotropic T cells homing to cancers maintain their proliferative and suppressive capacities, in particular in the light of the recognition of tumor and/or commensal antigens (Task 3). Altogether, this approach will lay the molecular and metabolic foundations governing the MAdCAM-1–α4β7 gut immune checkpoint
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
- medical and health sciences basic medicine pharmacology and pharmacy pharmaceutical drugs antibiotics
- 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-2023-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.
94805 Villejuif
France
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.