HEИндивидуална стипендия2023–2024

MOTM · Metabolic optimisation of intra-tumoral T cell motility

„Хоризонт Европа“ — Действия „Мария Склодовска-Кюри“

Период: 2023-01-01 → 2024-12-31
Финансиране от ЕС: 211 755 €
Участници: 1
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Метаболизмът на Т-клетките и начинът, по който те се движат в 3D среда, се анализират, за да се разбере защо често остават блокирани в тъканите около тумора. Това помага за подобряване на имунотерапията при пациенти със солидни ракови тумори.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Metabolic optimisation of intra-tumoral T cell motility

Immunotherapies have transformed cancer treatment. However, only a minority of patients with solid cancers responds to these approaches, partly due to the complex environment of human tumors. In human solid cancer, tumor cells frequently lie within tumor islets surrounded by a stroma composed of fibers and host-derived cells that prevent T cells from efficiently making contact with tumor cells for their killing. In order to improve current immunotherapies, it is crucial to understand the molecular and cellular mechanisms underlying T cell sequestration in the tumor stroma to design innovative strategies rendering T cell successful in entering tumor islets. Metabolism controls several T cell functions, and it also sustains cell migration by supplying energy through glycolysis or oxidative phosphorylation (OXPHOS). Although the role of cellular metabolism in regulating the migration and formation of metastasis of cancer cells is well known, we currently ignore how metabolism regulates T cell migration in complex environment. Few studies have so far addressed this point, but they mostly used 2D in vitro systems, which are not adapted to investigate the 3D motility of T cells in a complex tumor microenvironment. Also, due to the unavailability of nutrients, the accumulation of waste products, the acid pH and the oxygen tension, T cell metabolism is severely altered within the tumor microenvironment. However, whether and how these deregulations precisely impact on intratumoral T cell motility is unknown. Therefore, the main objectives of the project were (i) to determine how metabolism regulates T cell 3D migration in complex environment, (ii) to understand whether and how metabolic alterations in the tumor microenvironment may impact on T cell motility and (iii) to identify new strategies to improve T cell intratumoral motility in the context of current immunotherapy approaches against solid cancer.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

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.

Оригинален текст от CORDIS (на английски).

Участници

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE · ParisКоординаторФранция