Project description
Reprogramming endothelial cells in cold tumours to enhance immunotherapy
Despite the success of immunotherapy, lung cancer remains the leading cause of cancer mortality due to ‘cold’ tumours that exclude immune infiltration. Recent research identifies endothelial cells in the tumour vasculature as active gatekeepers that use mutation-driven, immunosuppressive gene signatures to block T-cell entry. Decoding these vascular barriers is essential for developing ‘reprogramming’ strategies that can convert resistant tumours into ones receptive to treatment. Supported by the Marie Skłodowska-Curie Actions programme, the noCOLDmore project will reprogramme endothelial cells in immune cold tumours to enhance immunotherapy responses. It will identify immunosuppressive gene signatures in endothelial cells, validate these targets in KL mice, and explore their therapeutic potential using a humanised orthotopic lung patient-derived xenograft model to advance immunotherapy.
Objective
Lung cancer is the leading cause of cancer-related deaths worldwide. Currently, immunotherapy (IT) is the standard of care for the treatment of some subtypes, with only nominal success. IT works best in inflamed “hot” tumors and is often ineffective in immune cell-desert “cold” tumors. In KRAS-mutated lung adenocarcinoma -LUAD, the most frequent type of lung cancer- the presence of a mutation in the STK11/LKB1 gene is linked to a cold tumor, while the co-occurrence of a TP53 mutation corresponds to a hot tumor. Amongst different cell types in the tumor environment impacting immune cell composition, endothelial cells (ECs) present an important and often overlooked modulator of immune profiles. Previous research has identified immunoregulatory genes expressed by ECs and proposed immuno-modulatory roles of ECs. I hypothesize that specific mutations cause the expression of immunosuppressive genes by ECs, which might explain the association of gene mutations affecting the immune environment. Thus, modulating ECs to reprogram them into immunostimulatory phenotypes in the immune cold tumors, could present a promising strategy to improve IT responses. To identify the immunosuppressive gene signature in ECs in immune cold vs hot tumors, I will utilize transgenic mouse models of LUAD: KrasG12D/+; Lkb1flox/flox (KL) and KrasG12D/+; Tp53flox/flox (KP) mice. First, using scRNAseq, I will establish an EC signature linked to the immune cold tumors and subsequently to identify EC-specific candidate immunosuppressive targets. After that, I will use state-of-the-art technologies that enable efficient gene targeting to validate the discovered targets in KL mice. I perform multidisciplinary approaches to delineate the molecular mode of action of the target exhibiting a substantial therapeutic effect in mice and overcoming the resistance to current anti-cancer IT. Finally, I will employ a humanized orthotopic lung PDX mouse model to further validate and test therapeutic opportunities.
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 prostate cancer
- medical and health sciences clinical medicine oncology lung cancer
- natural sciences biological sciences genetics mutation
- medical and health sciences basic medicine immunology immunotherapy
You need to log in or register to use this function
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.
-
HORIZON.1.2 - Marie Skłodowska-Curie Actions (MSCA)
MAIN PROGRAMME
See all projects funded under this programme
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-TMA-MSCA-PF-EF - HORIZON TMA MSCA Postdoctoral Fellowships - European Fellowships
See all projects funded under this funding scheme
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) HORIZON-MSCA-2023-PF-01
See all projects funded under this callCoordinator
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.
9052 ZWIJNAARDE - GENT
Belgium
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.