Biology subjects

Juhel, T.

Publications and source records attributed to Juhel, T..

4 recordsLinked to original sources

bioRxiv2026

Targeting the senescence-associated immune checkpoint GD3 ganglioside extends healthspan and blunt age-related diseases with sex-specific benefits.

The accumulation and impact of senescent cells in age-related diseases are increasingly characterized. However, the mechanisms underlying their accumulation and their causative role in age-associated pathologies remain poorly understood. We recently demonstrated that senescent cells can evade immune surveillance by regulating the expression of cell surface molecules such as the disialylated ganglioside GD3, which acts as a senescence-associated immune checkpoint (SIC) 1-3. Targeting GD3 therefore represents a novel therapeutic opportunity for age-related diseases. Here, we examined the effects of short-term anti-GD3 antibody treatment in mid-life on aging and age-related diseases in male and female mice, revealing striking sex-specific benefits. Treatment improved healthspan, survival (+20%) and reduced non-cancer mortality in males, while in females it reduced cancer-specific mortality without significantly affecting overall survival. Anti-GD3 treatment also mitigated fibrosis in lung, liver, and kidney tissues with distinct sex-dependent responses. Importantly, these benefits persisted for over a year after treatment cessation. These findings suggest that GD3-targeted therapy holds promise as a precision approach for treating age-related diseases, with therapeutic outcomes that depend critically on biological sex.

cell biology↗

bioRxiv2022

Activation of the P2RX7/IL-18 pathway in immune cells inhibits lung fibrosis

Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease associated with progressive and irreversible deterioration of respiratory functions that lacks curative therapies. Despite IPF being associated with a dysregulated immune response, current antifibrotics aim only at limiting fibroproliferation. We show here that the P2RX7/IL-18/IFNG axis is downregulated in IPF patients and that P2RX7 has immunoregulatory functions. Using our positive modulator of P2RX7, we show that activation of the P2RX7/IL-18 axis in immune cells limits lung fibrosis progression in a mouse model by favoring an anti-fibrotic immune environment, with notably an enhanced IL-18-dependent IFN-{gamma} production by lung T cells leading to a decreased production of IL-17 and TGF{beta}. Overall, we show the ability of the immune system to limit lung fibrosis progression by targeting the immunomodulator P2RX7. Hence, treatment with a small activator of P2RX7 may represent a promising strategy to help patients with lung fibrosis.

immunology↗

bioRxiv2021

Processing body dynamics drive non-genetic MEK inhibitors tolerance by fine-tuning KRAS and NRAS translation

Overactivation of the Mitogen-activated protein kinase (MAPK) pathway is a critical driver of many human cancers. However, therapies targeting this pathway have proven effective in only a few cancers, as cancers inevitably develop resistance. Puzzling observations suggest that MAPK targeting fails in tumors due to early compensatory RAS overexpression, albeit by unexplained mechanisms. We identified a novel mechanism of drug tolerance to MEK inhibitors (MEKi) that involves Processing Bodies (PBs), a membraneless organelle (MLO). MEKi promoted translation of the oncogenes KRAS and NRAS, which in turn triggered BRAF phosphorylation. This overexpression, which occurred in the absence of neotranscription, depended on PB dissolution as the source of the RAS mRNA. Moreover, in response to MEKi removal, the process was dynamic as PBs rapidly reformed and reduced MAPK signaling. These results highlight a dynamic spatiotemporal negative feedback loop of MAPK signaling via RAS mRNA sequestration. Furthermore, we observed a phenotype with a low number of PBs along with strong KRAS and NRAS induction capacities. Overall, we describe a new intricate mechanism involving PBs in the translational regulation of essential cellular signaling pathways like MAPKs, paving the way for future therapies altering MLO and thereby improving targeted cancer therapies.

cancer biology↗

bioRxiv2020

Small-molecule P2RX7 activator sensitizes tumor to immunotherapy and vaccinates mouse against tumor re-challenge

Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop new therapeutic strategies to improve patient outcome. We developed a new chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates PD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7 expressing cells to generate IL-18 which leads to the production of IFN-{gamma} by Natural Killer and CD4+ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a promising novel strategy that may be active against NSCLC.

cancer biology↗