Biology subjects

Feuillet, V.

Publications and source records attributed to Feuillet, V..

3 recordsLinked to original sources

bioRxiv2020

cAMP bursts control T cell directionality by actin cytoskeleton remodeling

T lymphocyte migration is an essential step to mounting an efficient immune response. The rapid and random motility of these cells which favors their sentinel role is conditioned by chemokines as well as by the physical environment. Morphological changes, underlaid by dynamic actin cytoskeleton remodeling, are observed throughout migration but especially when the cell modifies its trajectory. Using dynamic cell imaging, we investigated the signaling pathways involved in T cell directionality control. We monitored cAMP variation concomitantly with actin distribution upon T lymphocyte migration and highlighted the fact that spontaneous bursts in cAMP starting from the leading edge, are sufficient to promote stable actin redistribution triggering trajectory modification.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗

bioRxiv2018

Blockade of β-adrenergic receptor signaling improves cancer vaccine efficacy through its effect on naive CD8+ T-cell priming

{beta}-adrenergic receptor ({beta}-AR) signaling, by acting directly on tumor cells and angiogenesis, has been showed to exert pro-tumoral effects. Growing evidence also suggests that {beta}-AR expressed by immune cells affect the associated anti-tumor immune response. However, how and where {beta}-AR signaling impinges the anti-tumor immune response is still unclear. Using a mouse model of vaccine-based immunotherapy, we show here that propranolol, a non-selective {beta}-blocker, strongly improved the efficacy of the vaccine by enhancing the frequency of CD8+ T lymphocytes infiltrating the tumor (TILs). However, propranolol had no obvious effect on the reactivity of CD8+ TILs, a result further strengthened by ex-vivo experiments showing that these cells are insensitive to AR signaling triggered by adrenaline or noradrenaline. In contrast, we show that naive CD8+ T cell activation was strongly inhibited by {beta}-AR signaling and that the beneficial effect of propranolol mainly occurred during their initial priming phase. We also demonstrate that the differential sensitivity of CD8+ TILs and naive CD8+ T cells is related to their activation status since in vitro-activated CD8+ T cells behaved similarly to CD8+ TILs, both exhibiting a down-regulation of the {beta}2-AR expression. These results reveal that the initial priming phase of the anti-tumor response in the tumor-draining lymph node is a decisive part of the suppressive effect of {beta}-AR signaling on the CD8+ T-cell response against cancer. These findings provide a rationale for the strategic use of clinically available {beta}-blockers in patients to improve cancer immunotherapies such as anti-cancer vaccination strategies.

immunology↗

bioRxiv2018

TGFβ blocks STING-induced IFNα/ β release and tumor rejection in spontaneous mammary tumors

Type I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA can induce a strong production of IFN/{beta} and the rejection of transplanted primary tumors. In the present study, we addressed whether targeting STING with DMXAA also leads to the regression of spontaneous MMTV-PyMT mammary tumors. We show that these tumors are refractory to DMXAA-induced regression. This is due to a blockade in the phosphorylation of IRF3 and the ensuing IFN/{beta} production. Mechanistically, we identified TGF{beta} abundant in spontaneous tumors, as a key molecule limiting this IFN-induced-tumor regression by DMXAA. Finally, blocking TGF{beta} restores the production of IFN by activated MHCII+ tumor-associated macrophages, and enables tumor regression induced by STING activation. On the basis of these findings, we propose that type I IFN-dependent cancer therapies could be greatly improved by combinations including the blockade of TGF{beta}.

cancer biology↗