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Cellular and molecular regulators of the pleiotropic activities of gamma delta T cells in the tumor microenvironment

Project description

Immune crosstalk at the tumour microenvironment

The immune system plays a central role in tumour progression and disease outcome. Accumulating evidence indicates that two subtypes of immune cells infiltrate the tumour microenvironment with opposing roles. Interferon γ-producing γδ T cells have an anti-tumour effect, whereas IL-17A-secreting γδ T cells support tumour growth. Scientists of the EU-funded GammaDeltaTME project will investigate the mechanisms underlying the balance between these antagonistic T cell subsets. For this purpose, they will analyse the immune cell crosstalk in the tumour microenvironment at the metabolic, transcriptomic and epigenetic levels. The project's results have the potential to foster innovative strategies for promoting anti-tumour T cell functions as a therapeutic intervention.

Objective

Immune cells constitute a major component of the tumor microenvironment (TME) that influence several aspects of cancer progression and outcome. The host laboratory has identified two distinct γδ T-cell subsets with opposing roles in tumor progression: whereas interferon-γ (IFN-γ)-producing γδ T-cells stimulate anti-tumor responses, IL-17A-secreting γδ T-cells promote angiogenesis and tumor growth. However, the cellular and molecular factors controlling the critical balance between these antagonistic subsets remain unknown.
The present proposal builds on subsequent relevant findings of the host laboratory, namely that neutrophils suppress IL-17A+ γδ T-cell proliferation, revealing an unanticipated neutrophil/γδ T-cell crosstalk in TME, and that on another side the metabolic resources may also play a critical role in γδ T-cell subsets.
Based on these foundations, within the present proposal we will:
a) identify TME cellular partners that determine the balance between IFN-γ+ and IL-17A+ γδ T-cells in several experimental models of cancer.
b) study the metabolic pathways employed by γδ T-cell subsets and the impact of manipulating those pathways on their balance within the TME
c) analyze the impact of immune crosstalk and metabolic resources on γδ T-cell subsets both at transcriptomic and epigenetic levels.
Overall, this project will provide conceptual advances that will foster innovative strategies to promote anti-tumor γδ cell functions at the expense of their pro-tumoral activities.

Keywords

Call for proposal

H2020-WF-2018-2020

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Sub call

H2020-WF-02-2019

Coordinator

INSTITUTO DE MEDICINA MOLECULAR JOAO LOBO ANTUNES
Net EU contribution
€ 159 815,04
Address
AVENIDA PROF EGAS MONIZ
1649 028 Lisboa
Portugal

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Region
Continente Área Metropolitana de Lisboa Área Metropolitana de Lisboa
Activity type
Research Organisations
Links
Total cost
€ 159 815,04