Biology subjects

Hough, K. P.

Publications and source records attributed to Hough, K. P..

2 recordsLinked to original sources

bioRxiv2025

Patient-Derived Three-Dimensional Lung Tumor Models to Evaluate Response to Immunotherapy

Novel preclinical models that better mimic the in vivo tumor microenvironment are needed for advanced understanding of tumor biology and resistance/response to therapy. Herein, we report development of a novel ex vivo patient-derived three-dimensional lung tumor model (3D-LTM), that maintains features of human extracellular matrix, cell-cell interactions, and tissue architecture to evaluate a rapid response to immune checkpoint inhibitors (ICI). Within this model system, we recapitulated the heterogeneity of response to immunotherapy observed in non-small cell lung cancer (NSCLC) patients and defined signatures associated with response for predicting early response of ICI in patients. Spatial transcriptomics of the 3D-LTMs identified positive correlation of CD8+ T cell populations, CD4+ memory T cells, mast cells, NK cells, endothelial cells and non-classical monocytes with response status, whereas macrophages negatively correlated with response status. Pathway analysis of gene expression showed that chemokine signaling related pathways were activated in responder 3D-LTM tissues, whereas suppression of antigen presentation-related pathways and activation of Treg differentiation-related pathways was associated with 3D-LTMs that were not considered responders. This model system has utility for rapid testing of novel immune directed therapy outcomes and for developing biomarkers of ICI response in NSCLC.

cancer biology↗

bioRxiv2024

Small Extracellular Vesicle Signaling and Mitochondrial Transfer Reprograms T Helper Cell Function in Human Asthma

Small extracellular vesicles (sEVs) are known to orchestrate cell-cell communication, but the role of sEV signaling via mitochondria in perpetuating asthmatic airway inflammation is unknown. Myeloid-derived regulatory cells (MDRCs) are known to control CD4+ T cell responses in asthma. We demonstrate that airway MDRC-derived sEVs from asthmatics mediate T cell receptor engagement and transfer of mitochondria that induce antigen-specific activation and polarization of Th17 and Th2 cells; these cells are drivers of chronic airway inflammation in asthma. CD4+ T cells internalize sEVs containing mitochondria predominantly by membrane fusion, and blocking mitochondrial oxidant signaling in MDRC-derived sEVs mitigates T cell activation. Reactive oxygen species-mediated signaling that elicits T cell activation in asthmatics is sEV-dependent. Additionally, a Drp1-dependent mechanism in pro-inflammatory MDRCs promotes mitochondrial packaging within sEVs, which then co-localize with the polarized cytoskeleton and mitochondrial networks in recipient T cells. Importantly, intranasal transfer of mitochondria packaged sEVs enhances airway inflammation and Th polarization in vivo in a murine model of asthma. Thus, our studies indicate a previously unrecognized role for mitochondrial fission and sEV-mediated mitochondrial transfer-mediated signaling in dysregulated T cell activation and Th cell polarization in asthma which could constitute a novel therapeutic target.

immunology↗