Biology subjects

Horswell, S.

Publications and source records attributed to Horswell, S..

4 recordsLinked to original sources

bioRxiv2024

Simulating CD8 T Cell Exhaustion: A Comprehensive Approach

Immunotherapy has revolutionised the treatment of multiple cancer types, however, these treatments only work for a proportion of patients and biomarkers to predict response are lacking. One correlate of response is the reinvigoration of a subset of CD8 T cells that have an exhausted phenotype and impaired functionality. In order to develop new therapies, reproducible models are required to identify candidate target genes that enables the reversal of key hallmarks of T cell exhaustion. Here we describe the development of an in vitro model by chronically stimulating T cells with their cognate antigen and performed an in depth temporal phenotypic characterisation. This model recapitulates many of the critical hallmarks of exhaustion, including increased expression of canonical exhaustion surface markers, impaired proliferation, reduced cytokine production, decreased release of cytotoxic granules, and metabolic alterations, including dysfunctional mitochondria. These exhaustion hallmarks were validated using an in vivo model and a gene signature identified which robustly define the shared in vitro and in vivo exhausted state. Critically, this signature is also observed in tumour infiltrating T cells from multiple human tumour types, validating the translational potential of this model for discovering and triaging new therapies.

immunology↗

bioRxiv2020

Transcriptomic characterization of tuberculous sputum reveals a host Warburg effect and microbial cholesterol catabolism

The crucial transmission phase of tuberculosis (TB) relies on infectious sputum yet cannot easily be modeled. We applied one-step RNA-Sequencing to sputum from infectious TB patients to investigate the host and microbial environments underlying transmission of Mycobacterium tuberculosis (Mtb). In such TB sputa, compared to non-TB controls, transcriptional upregulation of inflammatory responses and a metabolic shift towards glycolysis was observed in the host. Amongst all bacterial sequences in the sputum, only less than 1.5% originated from Mtb and its abundance is associated with HIV-1 coinfection status. The transcriptome of sputum Mtb more closely resembled aerobic replication and was characterized by evidence of cholesterol utilization, zinc deprivation and reduced expression of the virulence-associated PhoP regulon. Our study provides a comprehensive analysis of the transcriptional landscape associated with infectious sputum and demonstrates the feasibility of applying advanced sequencing technology to readily accessible pathological specimens in the study of host-pathogen adaptation.

microbiology↗

bioRxiv2020

Enteric glia as a source of neural progenitors in adult zebrafish

The presence and identity of neural progenitors in the enteric nervous system (ENS) of vertebrates is a matter of intense debate. Here we demonstrate that the non-neuronal ENS cell compartment of teleosts shares molecular and morphological characteristics with mammalian enteric glia but cannot be identified by the expression of canonical glia markers. However, unlike their mammalian counterparts, which are generally quiescent and do not undergo neuronal differentiation during homeostasis, we show that a relatively high proportion of zebrafish enteric glia proliferate under physiological conditions giving rise to progeny that differentiate into enteric neurons. We also provide evidence that, similar to brain neural stem cells, the activation and neuronal differentiation of enteric glia are regulated by Notch signalling. Our experiments reveal remarkable similarities between enteric glia and brain neural stem cells in teleosts and open new possibilities for use of mammalian enteric glia as a potential source of neurons to restore the activity of intestinal neural circuits compromised by injury or disease.

neuroscience↗

bioRxiv2019

Inherited duplications of PPP2R3B promote naevi and melanoma via a novel C21orf91-driven proliferative phenotype

The majority of the heredity of melanoma remains unexplained, however inherited copy number changes have not yet been systematically studied. The genetic environment is highly relevant to treatment stratification, and new gene discovery is therefore desirable. Using an unbiased whole genome screening approach for copy number we identify here a novel melanoma predisposing factor, familial duplications of gene PPP2R3B, encoding a regulatory unit of critical phosphatase PP2A. Significant correlation between expression of PPP2R3B in tumour tissue and survival in a large melanoma cohort was confirmed, and associated with a non-immunological expression profile. Mechanistically, construction and extensive characterization of a stable, inducible cellular model for PPP2R3B overexpression revealed induction of pigment cell switching towards proliferation and away from migration. Importantly, this was independent of the known microphthalmia-associated transcription factor (MITF)-controlled pigment cell phenotype switch, and was instead driven by uncharacterised gene C21orf91. Bioinformatic studies point to C21orf91as a novel target of MITF, and therefore a potential hub in the control of phenotype switching in melanoma. This study identifies novel germline copy number variants in PPP2R3B predisposing to melanocytic neoplasia, and uncovers a new potential therapeutic target C21orf91 in the control of pigment cell proliferation.

genomics↗