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

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 TMEc) 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.