Biology subjects

West, N. R.

Publications and source records attributed to West, N. R..

4 recordsLinked to original sources

bioRxiv2026

Inhibition of integrin αvβ8-mediated TGFβ activation and active-TGFβ blockade promote anti-tumor immunity through distinct biological mechanisms

Transforming Growth Factor {beta} (TGF{beta}) is a potent immunosuppressor and a primary driver of resistance to cancer immunotherapy. While preclinical models have long suggested that TGF{beta} inhibition could synergize with immune checkpoint inhibitors, these effects have proven difficult to replicate in clinical settings. The highly regulated TGF{beta} pathway can be inhibited through various mechanisms, including neutralizing activated ligands or inhibiting upstream activators, such as integrins. Recent structural data demonstrated that integrin v{beta}8 can enable TGF{beta}1/3 signaling without releasing the active cytokines from their Latency-Associated Peptides, suggesting that ligand-blocking antibodies may have limited access to their epitopes. Here, we show that integrin v{beta}8 blockade, while achieving anti-tumor responses similar to those of anti-TGF{beta} antibodies, does so through a distinct mechanism of action. Anti-v{beta}8 is 3 orders of magnitude more potent at inhibiting v{beta}8-mediated TGF{beta} activity than a commonly used antibody against the mature form of the cytokine. Whereas TGF{beta} ligand inhibition has little effect on TGF{beta} signaling in tumor-draining lymph nodes (tdLN) and requires IFN{gamma} for its anti-tumor effects, v{beta}8 blockade strongly inhibits TGF{beta} signaling in tdLN and, in combination with PD-L1 blockade, drives tumor control through an IFN{gamma} -independent mechanism that strictly requires T cell egress from tdLN. Combined v{beta}8 and anti-PD-L1 blockade enhances antigen presentation in dendritic cells (DCs) and, unlike TGF{beta} ligand blockade, improves the efficiency of DC-induced T cell activation in response to cross-presented antigen. These findings suggest that v{beta}8 blockade can disable an immunologically critical source of TGF{beta} signaling that is not addressed by antibodies targeting TGF{beta} ligands, suggesting a promising new approach to TGF{beta} pathway modulation. One Sentence SummaryUnlike ligand-neutralizing antibodies, v{beta}8 blockade suppresses TGF{beta} in tdLN and boosts DC-T cell activation, a differentiated immunotherapy strategy.

immunology↗

bioRxiv2025

Combined antagonism of Oncostatin M (OSM) and Interleukin 6 (IL-6) provides both anti-fibrotic and anti-inflammatory benefit in pulmonary fibrosis

Interstitial lung diseases (ILDs), including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated ILD (SSc-ILD), are irreversible fibrosing diseases with a mean survival time of less than 5 years for IPF. Poorly understood etiology and complex pathogenesis of these diseases have hampered the identification and development of effective therapeutics. Existing treatments can slow progressive fibrosis and lung function decline but do not stop it entirely, resulting in a minimal impact on patient survival. Thus, novel therapeutic interventions are needed. Tocilizumab, an anti-IL-6 receptor antibody, was recently approved by FDA for the treatment of SSc-ILD based on evidence demonstrating a reduction in the rate of lung function decline. In this study, we have characterized an IL-6-driven feed-forward myeloid axis contributing to lung inflammation providing a mechanistic hypothesis for tocilizumab. Concomitantly we have identified an oncostatin M (OSM) orchestrated lung injury response contributing to epithelial and endothelial cell disruption, myofibroblast activation and fibrosis. Despite dysregulated expression of IL11 in IPF, SSc-ILD, and murine models of fibrosis, we found no evidence for a pro-fibrotic role for IL-11 in vitro or in vivo. Instead, in pre-clinical models of IPF we demonstrate that antagonism of OSM alone, or to a greater degree in combination with IL-6, reduced lung fibrosis and inflammation. Translating these observations, we validated gp130:OSMR, rather than gp130:LIFR, as the dominant human receptor complex used by OSM, identifying OSMR as a potential therapeutic target to stall fibrosis.

immunology↗

bioRxiv2025

Single-nucleus analysis reveals dysregulated oxidative phosphorylation in Down syndrome basal forebrain at birth

INTRODUCTIONBasal forebrain cholinergic neurons (BFCNs) are integral to learning, attention, and memory, and are prone to degeneration in Down syndrome (DS), Alzheimers disease, and other neurodegenerative diseases. However, the mechanisms that lead to the degeneration of these neurons are not known. METHODSSingle-nucleus gene expression and ATAC sequencing were performed on postmortem human basal forebrain from unaffected control and DS tissue samples at 0-2 years of age (n=4 each). RESULTSSequencing analysis of postmortem human basal forebrain identifies gene expression differences in DS early in life. Genes encoding proteins associated with energy metabolism pathways, specifically oxidative phosphorylation and glycolysis, and genes encoding antioxidant enzymes are upregulated in DS BFCNs. DISCUSSIONMultiomic analyses reveal that energy metabolism may be disrupted in DS BFCNs by birth. Increased oxidative phosphorylation and the accumulation of reactive oxygen species byproducts may be early contributors to DS BFCN neurodegeneration.

neuroscience↗

bioRxiv2016

Effect of obesity-linked FTO rs9939609 variant on physical activity and dietary patterns in physically active men and women

ObjectiveTo examine physical activity and dietary patterns in physically active individuals carrying different risk variants of the fat mass and obesity-associated gene (FTO) rs9939609 single nucleotide polymorphism (SNP).\n\nMethodsA total of 528 white men and women (mean (SD): 34.9(9.5) years, 26.6(4.3) kg{middle dot}m-2) were genotyped for FTO rs9939609 SNP. Sex, age and anthropometric measurements (stature, body mass, waist circumference) were self-reported using an online questionnaire, and body mass index and waist-to-height ratio were calculated. Physical activity level and eating behaviour were assessed using the International Physical Activity Questionnaire and Three-Factor Eating Questionnaire (TFEQ), respectively.\n\nResultsBody mass, body mass index, waist circumference and waist-to-height ratio were not significantly different between individuals carrying different FTO rs9939609 risk variants (all P[≥]0.66). The cohort was physically active (4516(3043) total MET min{middle dot}week-1), although risk allele carriers (AT/AA) reported higher total physical activity (effect size = 0.22, p=0.03), and homozygous risk allele carriers (AA) displayed higher TFEQ cognitive restraint (effect size = 0.33, p=0.03) compared with non-risk allele carriers (TT).\n\nConclusionsObesity-related parameters were not different in physically active individuals carrying different risk variants of FTO rs9939609, but higher physical activity and cognitive restraint in risk allele carriers may reduce genetic predisposition to weight gain.

genetics↗