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Metabolic optimisation of intra-tumoral T cell motility

Background. The tumor microenvironment markedly limits intra-tumoral T cell motility and the contact with tumor cells. Such a defective intra-tumoral motility of T cells is one of the main reasons explaining why current treatments... ver más

31/12/2024

INSERM

212K€

Presupuesto del proyecto: 212K€

Líder del proyecto

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHER... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Ver 1 Participantes

Financiación concedida El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2022-07-22

Línea de financiación objetivo El proyecto se financió a través de la siguiente ayuda:

HORIZON-MSCA-2021-PF-01-01: MSCA Postdoctoral Fellowships 2021

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INSERM

211.75K€ | Lider

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Duración del proyecto: 29 meses Fecha Inicio: 2022-07-22
Fecha Fin: 2024-12-31

Presupuesto del proyecto 212K€

Descripción del proyecto Background. The tumor microenvironment markedly limits intra-tumoral T cell motility and the contact with tumor cells. Such a defective intra-tumoral motility of T cells is one of the main reasons explaining why current treatments based on reinvigoration/infusion of T cells to fight human solid cancers are unsuccessful. Metabolic reactions support T cell migration. Although T cell metabolism is severely de-regulated within different tumor areas, how this specifically affects intra-tumoral T cell motility is unknown. This aspect is important, since the metabolism of tumor-infiltrating T cells could be in principle easily modulated, opening a window of opportunity to improve current immunotherapy approaches against solid cancers, whose ineffectiveness is often associated with a poor intra-tumoral T cell motility. Objectives. I want to understand (i) which are the metabolic determinants of T cell motility, (ii) how the metabolic alterations within the TME affect T cell motility, and (iii) how to manipulate the metabolism of T cells and CAR T cells to improve their intra-tumoral motility and anti-cancer response. Main Methodologies. Viable tissue slices from human and murine tumors will be used to measure intra-tumoral T cell motility (real-time imaging microscopy) and metabolism (multiparameter imaging approaches, spatial gene expression, histo-cytometry) and to assess the consequences of the manipulation of the metabolic milieu on T cell distribution and motility. Also, CAR T cells will be engineered with new metabolism modules to improve their infiltration into solid tumor. Expected Results. The findings of this project will provide new insights into (i) how to improve the metabolic regimen of human solid cancer patients to increase T cell infiltration into tumor islets, and (ii) how to improve the infiltration of CAR T cells during adoptive cell immuno-therapy approaches by modulating their metabolism.

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