Biology subjects

Henderson, S.

Publications and source records attributed to Henderson, S..

23 records · Page 2Linked to original sources

bioRxiv2020

Pro-metastatic gene expression, immune evasion and an altered HPV spectrum characterize an aggressive subtype of cervical cancer

Human papillomavirus (HPV)-associated cervical cancer represents one of the leading causes of cancer death worldwide. Although low-middle income countries are disproportionately affected, our knowledge of the disease predominantly originates from populations in high-income countries. Using the largest multi-omic analysis of cervical squamous cell carcinoma (CSCC) to date, totalling 643 tumours and representing patient populations from the USA, Europe and Sub-Saharan Africa, we identify two CSCC subtypes (C1 and C2) with differing prognosis. C1 tumours are largely HPV16-driven, display increased cytotoxic T-lymphocyte infiltration and frequently harbour PIK3CA and EP300 mutations. C2 tumours are associated with shorter overall survival, are frequently driven by HPVs from the HPV18-containing alpha-7 clade, harbour alterations in the Hippo signalling pathway and increased expression of immune checkpoint genes, B7-H3 (also known as CD276) and NT5E (also known as CD73) and PD-L2 (also known as PDCD1LG2). In conclusion, we identify two novel, therapy-relevant CSCC subtypes that share the same defining characteristics across three geographically diverse cohorts.

cancer biology↗

bioRxiv2019

A novel antibody targeting ICOS increases intratumoural cytotoxic to regulatory T cell ratio and induces tumour regression.

The immunosuppressive tumour microenvironment constitutes a significant hurdle to the response to immune checkpoint inhibitors. Both soluble factors and specialised immune cells such as regulatory T cells (TReg) are key components of active intratumoural immunosuppression. Previous studies have shown that Inducible Co-Stimulatory receptor (ICOS) is highly expressed in the tumour microenvironment, especially on TReg, suggesting that it represents a relevant target for preferential depletion of these cells. Here, we used immune profiling of samples from tumour bearing mice and cancer patients to characterise the expression of ICOS in different tissues and solid tumours. By immunizing an Icos knockout transgenic mouse line expressing antibodies with human variable domains, we selected a fully human IgG1 antibody called KY1044 that binds ICOS from different species. Using KY1044, we demonstrated that we can exploit the differential expression of ICOS on T cell subtypes to modify the tumour microenvironment and thereby improve the anti-tumour immune response. We showed that KY1044 induces sustained depletion of ICOShigh TReg cells in mouse tumours and depletion of ICOShigh T cells in the blood of non-human primates, but was also associated with secretion of pro-inflammatory cytokines from ICOSlow TEFF cells. Altogether, KY1044 improved the intratumoural TEFF:TReg ratio and increased activation of TEFF cells, resulting in monotherapy efficacy or in synergistic combinatorial efficacy when administered with the immune checkpoint blocker anti-PD-L1. In summary, our data demonstrate that targeting ICOS with KY1044 can favourably alter the intratumoural immune contexture, promoting an anti-tumour response.

cancer biology↗

bioRxiv2019

Human Oocytes Harbouring Damaged DNA Can Complete Meiosis-I

Chromosomal abnormalities such as aneuploidies and DNA damage are considered a major threat to the establishment of healthy eggs and embryos. Recent landmark studies showed that mouse oocytes with damaged DNA can resume meiosis and undergo Germinal Vesicle Breakdown (GVBD), but then arrest in metaphase of meiosis-I in a process involving Spindle Assembly Checkpoint (SAC) signalling. Such a mechanism could help prevent the generation of metaphase-II (Met-II) eggs with damaged DNA. However we report that this is not the case in the human oocyte. DNA damage prevents human oocytes from undergoing GVBD in some cases. Strikingly however, most oocytes harbouring DNA damage progress through meiosis-I and subsequently extrude the first polar body (PB1) to form a metaphase-II egg, revealing the absence of a DNA-damage-induced SAC response. Analysis of the resulting metaphase-II eggs revealed highly disorganised spindles with misaligned and heavily damaged chromosomes. Our results suggest that DNA damage accumulated in meiosis-I, such as could occur during in vitro maturation procedures, does not prevent polar body extrusion and therefore could persist in morphologically normal looking metaphase-II eggs.

developmental biology↗

bioRxiv2019

Role for Merlin/NF2 in transcription elongation through interaction with the PAF complex

The PAF complex (PAFC) coordinates transcription elongation and mRNA processing events and its CDC73/parafibromin subunit functions as a tumour suppressor. The NF2/Merlin tumour suppressor functions at the cell cortex and nucleus and is a key mediator of contact inhibition. Here we provide a direct link between nuclear Merlin and transcription elongation controlled by cell-cell adhesion. Merlin interacts with the PAFC in a cell density-dependent manner and tumour-derived inactivating mutations in both Merlin and CDC73 mutually disrupt their interaction. Growth suppression by Merlin requires CDC73 and Merlin regulates PAFC association with chromatin in a subset of genes. We also identify by CDC73 affinity-proteomics a role for FAT cadherins in regulating the Merlin-PAFC interaction. Our results suggest that in addition to its function within the Hippo pathway, nuclear Merlin is part of a tumour suppressor network which coordinates postinitiation steps of the transcription cycle of genes mediating in contact inhibition.

cancer biology↗

bioRxiv2019

A method for non-invasive prenatal diagnosis of monogenic autosomal recessive disorders

Non-invasive prenatal testing (NIPT) to date is used in the clinic primarily to detect foetal aneuploidy. Few studies so far have focused on the detection of monogenic autosomal recessive disorders where mother and foetus carry the same mutation. In particular, NIPT is currently not available for the detection of Sickle Cell Anaemia (SCA), the most common monogenic disorder world-wide and the most common indication for invasive prenatal testing in high-income countries. Here, we report the clinical validation of a novel diagnostic approach that combines ultra-sensitive amplicon-based sequencing of cell-free DNA (cfDNA) with internal controls and bias factor correction to calculate the probability for the presence of allelic imbalance from maternal plasma without prior knowledge of the paternal genotype. Identification of the foetal genotype was determined using a hierarchical probabilistic model based on the relative number of reads from the sequencing, along with the foetal fraction. NIPT was performed on a cohort of 57 patients, all of whom had previously undergone invasive prenatal testing so that the foetal genotype was known. Overall, NIPT demonstrated 100% sensitivity and negative predictive value for foetal fractions higher than 0.5%, and 100% specificity and positive predictive value for foetal fractions higher than or equal to 4%. Our methodology can be used as a safe, non-invasive screening tool in any clinical scenarios where early prenatal diagnosis of SCA or other recessive disorders is important.

genomics↗