Biology subjects

Hahn, P.

Publications and source records attributed to Hahn, P..

4 recordsLinked to original sources

bioRxiv2026

Patient-derived ascites reveals functional advantages of γδCAR T-cells within the ovarian cancer-like tumor microenvironment

Chimeric antigen receptor (CAR) T-cells engineered from {gamma}{delta} T-cells show limited clinical benefit in solid tumors such as ovarian cancer (OVCA). Although {gamma}{delta} T-cells can detect malignant transformation and exert cytotoxicity, these properties confer potent preclinical efficacy but limited therapeutic activity and the basis for this discrepancy remains unclear. Here, we established an ex-vivo culture consisting of highly inflammatory patient-derived malignant ascites and hypoxia conditions, to simulate key obstacles encountered by CAR T-cells in the immunosuppressive OVCA tumor microenvironment (TME). Using this condition, we first demonstrated the presence of CAR-expressing {gamma}{delta} T-cells within conventional (conv)CAR T-cells, which displayed greater proliferative capacity than {gamma}{delta}neg T-cells. We therefore produced {gamma}{delta}CAR T-cells for parallel comparison with conventional (conv)CAR T-cells, evaluating differences in gene expression and functionality. Under TME-like conditions, {gamma}{delta}CAR T-cells demonstrated lower viability but consistently outperformed convCAR T-cells, demonstrating favorable gene expression profiles, enhanced cytotoxicity, improved retention of cytokine secretion and degranulation and increased proliferative capacity. Importantly, we characterized an ascites protein profile that impacted the viability of both cell types comparably. Together, these findings reveal specific functional advantages of {gamma}{delta}CAR T-cells over convCAR T-cells in the immunosuppressive OVCA TME-like condition while facing different cellular fitness constraints, providing insights into the use and limitations of {gamma}{delta}CAR T-cells.

immunology↗

bioRxiv2022

YAP and collagen remodelling support cell proliferation and tumour aggressiveness in uterine leiomyosarcoma

Fibrillar collagen deposition, stiffness, and downstream signalling support the development of leiomyomas (LM), common benign mesenchymal tumours of the uterus, and are associated with aggressiveness in multiple carcinomas. Compared to epithelial carcinomas, however, the impact of fibrillar collagens on malignant mesenchymal tumours, including uterine leiomyosarcoma (LMS), remains elusive. In this study, we analyse the network morphology and density of fibrillar collagens combined with the gene expression of LMS, LM and normal myometrium (MM). We find that, in contrast to LM, LMS tumours present low collagen density and increased expression of collagen-remodelling genes, features associated with tumour aggressiveness. Using collagen-based 3D matrices, we show that the activity of MMP14, a central protein with collagen-remodelling functions particularly overexpressed in LMS, is necessary for LMS cell proliferation. In addition, we find that, unlike MM and LM cells, LMS proliferation and migration are not affected by collagen substrate stiffness. We demonstrate that LMS cell growth in low matrix adhesion microenvironments is supported by an enhanced basal YAP activity. Altogether, our results indicate that LMS cells acquire high collagen remodelling capabilities and are adapted to grow and migrate in low collagen and soft microenvironments. These results further suggest that matrix remodelling and YAP are potential therapeutic targets for this deadly disease.

cancer biology↗

bioRxiv2021

Cell-extrinsic autophagy in mature adipocytes regulates anti-inflammatory response to intestinal tissue injury through lipid mobilization

Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, through their use as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte-specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti- inflammatory energy substrates. Instead, Atg7-deficient adipose tissues exhibited an altered oxylipin balance, driven through an NRF2-mediated upregulation of Ephx1. This was accompanied by a shift in adipose tissue macrophage polarization with reduced secretion of IL-10, leading to lower circulating levels of IL-10. These results suggest an underappreciated fat-gut crosstalk through an autophagy- dependent regulation of anti-inflammatory oxylipins, indicating a protective effect of adipose tissues for distant inflammation.

immunology↗

bioRxiv2019

VIP-producing enteric neurons interact with innate lymphoid cells to regulate feeding-dependent intestinal epithelial barrier functions

The intestinal mucosa serves as both a conduit for uptake of food-derived nutrients and microbiome-derived metabolites and as a barrier that prevents tissue invasion by microbes and tempers inflammatory responses to the myriad contents of the lumen. How the intestine coordinates physiological and immune responses to food consumption to optimize nutrient uptake while maintaining barrier functions remains unclear. Here, we describe how a gut neuronal signal triggered by food intake is integrated with intestinal antimicrobial and metabolic responses controlled by type 3 innate lymphoid cells (ILC3)1-3. Food consumption rapidly activates a population of enteric neurons that express vasoactive intestinal peptide (VIP)4. Projections of VIP-producing neurons (VIPergic neurons) in the lamina propria are in close proximity to clusters of ILC3 that selectively express VIP receptor type 2 (VIPR2 or VPAC2). ILC3 production of IL-22, which is up-regulated by commensal microbes such as segmented filamentous bacteria (SFB)5-7, is inhibited upon engagement of VIPR2. As a consequence, there is a reduction in epithelial cell-derived antimicrobial peptide, but enhanced expression of lipid-binding proteins and transporters8. During food consumption, activation of VIPergic neurons thus enhances growth of epithelial-associated SFB and increases lipid absorption. Our results reveal a feeding- and circadian-regulated dynamic intestinal neuro-immune circuit that promotes a trade-off between IL-22-mediated innate immune protection and efficiency of nutrient absorption. Modulation of this pathway may hence be effective for enhancing resistance to enteropathogen2,3,9 and for treatment of metabolic diseases.

immunology↗