Crispin Hiley

Crispin Hiley
The Francis Crick Institute

MBChB, PhD, MRCP, FRCR

About

72
Publications
20,661
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10,735
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Introduction
Crispin Hiley currently works at The Francis Crick Institute. Crispin does research in Oncology, Genetics and Cell Biology. Their current project is 'TRACER-x'.

Publications

Publications (72)
Article
Full-text available
The growing scale and dimensionality of multiplexed imaging require reproducible and comprehensive yet user-friendly computational pipelines. TRACERx-PHLEX performs deep learning-based cell segmentation (deep-imcyto), automated cell-type annotation (TYPEx) and interpretable spatial analysis (Spatial-PHLEX) as three independent but interoperable mod...
Article
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The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53 , are mo...
Article
Understanding the role of the tumor microenvironment (TME) in lung cancer is critical to improving patient outcomes. We identified four histology-independent archetype TMEs in treatment-naïve early-stage lung cancer using imaging mass cytometry in the TRACERx study (n = 81 patients/198 samples/2.3 million cells). In immune-hot adenocarcinomas, spat...
Article
Circulating tumour DNA (ctDNA) can be used to detect and profile residual tumour cells persisting after curative intent therapy1. The study of large patient cohorts incorporating longitudinal plasma sampling and extended follow-up is required to determine the role of ctDNA as a phylogenetic biomarker of relapse in early-stage non-small-cell lung ca...
Article
Lung adenocarcinomas (LUADs) display a broad histological spectrum from low-grade lepidic tumors through to mid-grade acinar and papillary and high-grade solid, cribriform and micropapillary tumors. How morphology reflects tumor evolution and disease progression is poorly understood. Whole-exome sequencing data generated from 805 primary tumor regi...
Article
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Metastatic disease is responsible for the majority of cancer-related deaths1. We report the longitudinal evolutionary analysis of 126 non-small cell lung cancer (NSCLC) tumours from 421 prospectively recruited patients in TRACERx who developed metastatic disease, compared with a control cohort of 144 non-metastatic tumours. In 25% of cases, metasta...
Article
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B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here...
Article
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Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint...
Article
Background: Lung adenocarcinoma (LUAD) is a morphologically and genetically diverse disease. The prognostic impact of LUAD histological patterns have been described, such as solid growth pattern and poor outcomes, though their underlying biology is poorly understood. Furthermore, the genomic characteristics and evolutionary constraints in relation...
Article
Background: Primary lung cancer is the leading cause of cancer-related mortality, with metastatic disease being responsible for the majority of deaths. To gain insight into the lethal process of metastasis, we report on the longitudinal evolutionary analysis of the TRACERx 421 paired primary-metastasis cohort. Methods: 712 tumor samples, of which 4...
Article
Introduction. Studying cell-to-cell variation within the tumour’s native context is crucial for fully understanding tumour heterogeneity and its impact on disease progression and therapy response. Tumour cells and their surrounding stromal cells can be spatially profiled using multiplex imaging with a growing number of detectable proteins. The meth...
Article
Immunotherapy containing regimens have become the standard of care first-line therapy for non-small cell lung cancer (NSCLC) in the metastatic setting and are being explored in the adjuvant and neo-adjuvant setting. However, as intratumor heterogeneity (ITH) is pervasive in cancer we investigated the impact of ITH on established and putative biomar...
Article
Background: The adaptive immune system plays an important role in tumor evolution. A key source of cytotoxic T cell response in cancer is neoantigens, cancer cell specific mutations that result in mutant peptides that elicit a T cell mediated immune response. However, a mutation can only engender a neoantigen if the associated mutant peptide is pre...
Conference Paper
Introduction: Mutations in the epidermal growth factor receptor (EGFR) are often found in never-smokers who develop lung adenocarcinoma (LUAD) and resistance to receptor-targeted tyrosine kinase inhibitors (TKIs) generally occurs within five years of treatment. Mixed responses, where individual tumor lesions within the same patient respond differen...
Article
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The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy1,2. However, measurements of tumour infiltrating lymphocytes (TILs) are limited by a shortage of appropriate data. Whole-exome sequencing (WES) of DNA is frequently performed to calculate tumour mutational burden and identify act...
Article
Aims: There is a paucity of evidence on which to produce recommendations on neither the clinical nor the imaging follow-up of lung cancer patients after curative-intent radiotherapy. In the 2019 National Institute for Health and Care Excellence lung cancer guidelines, further research into risk-stratification models to inform follow-up protocols w...
Article
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Remarkable progress in molecular analyses has improved our understanding of the evolution of cancer cells toward immune escape1–5. However, the spatial configurations of immune and stromal cells, which may shed light on the evolution of immune escape across tumor geographical locations, remain unaddressed. We integrated multiregion exome and RNA-se...
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
Full-text available
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Article
Remarkable progress in molecular analyses has improved our understanding of the evolution of cancer cells toward immune escape1,2,3,4,5. However, the spatial configurations of immune and stromal cells, which may shed light on the evolution of immune escape across tumor geographical locations, remain unaddressed. We integrated multiregion exome and...
Article
Full-text available
Tumour mutational burden (TMB) predicts immunotherapy outcome in non-small cell lung cancer (NSCLC), consistent with immune recognition of tumour neoantigens. However, persistent antigen exposure is detrimental for T cell function. How TMB affects CD4 and CD8 T cell differentiation in untreated tumours and whether this affects patient outcomes is u...
Article
Patients treated with curative-intent lung radiotherapy are in the group at highest risk of severe complications and death from COVID-19. There is therefore an urgent need to reduce the risks associated with multiple hospital visits and their anti-cancer treatment. One recommendation is to consider alternative dose-fractionation schedules or radiot...
Article
Full-text available
Tumor-targeting oncolytic viruses such as Vaccinia virus (VV) are attractive cancer therapeutic agents that act through multiple mechanisms to provoke both tumor lysis and anti-tumor immune responses. However, delivery of these agents remains restricted to intra-tumoral administration, which prevents effective targeting of inaccessible and dissemin...
Article
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Somatic mutations together with immunoediting drive extensive heterogeneity within non-small-cell lung cancer (NSCLC). Herein we examine heterogeneity of the T cell antigen receptor (TCR) repertoire. The number of TCR sequences selectively expanded in tumors varies within and between tumors and correlates with the number of nonsynonymous mutations....
Article
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An aim of molecular biomarkers is to stratify patients with cancer into disease subtypes predictive of outcome, improving diagnostic precision beyond clinical descriptors such as tumor stage¹. Transcriptomic intratumor heterogeneity (RNA-ITH) has been shown to confound existing expression-based biomarkers across multiple cancer types2,3,4,5,6. Here...
Article
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TOURIST: Thoracic Umbrella Radiotherapy study in stage IV NSCLC: A phase III randomised trial in development Woolf D, Lee C, Shah R, Ahned M, Fraser I, BIllinghamL, Philips I, McAleese J, Hiley C, Taylor A, Calman L, Barton R, Hatton M. Background Non Small Cell Lung Cancer (NSCLC) is the leading cause of cancer mortality throughout the world wi...
Conference Paper
At the point of cancer diagnosis, molecular biomarkers aim to stratify patients into precise disease subtypes predictive of outcome independent of standard clinical parameters such as tumour stage. Although prognostic gene expression signatures have been derived for many cancer types, seldom have they been shown to improve therapeutic decision maki...
Conference Paper
At the point of cancer diagnosis, molecular biomarkers aim to stratify patients into precise disease subtypes predictive of outcome independent of standard clinical parameters such as tumour stage. Although prognostic gene expression signatures have been derived for many cancer types, seldom have they been shown to improve therapeutic decision maki...
Article
2590 Background: CD4 T helper cells are key orchestrators of immunity in states of persistent antigen exposure. In chronic viral infection, loss of immune control is associated with CD4 differentiation skewing (CD4 ds ) resulting from decline of early progenitors and gain in abundance of exhausted and terminally differentiated subsets. Here, we set...
Article
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The interplay between an evolving cancer and a dynamic immune microenvironment remains unclear. Here we analyse 258 regions from 88 early-stage, untreated non-small-cell lung cancers using RNA sequencing and histopathology-assessed tumour-infiltrating lymphocyte estimates. Immune infiltration varied both between and within tumours, with different m...
Conference Paper
In order to avoid immune predation, particularly in response to immunotherapy, tumors must acquire mechanisms to evade immune detection or withstand its activity. Disruption of human leukocyte antigen (HLA), which may lead to reduced neoantigen presentation, has been proposed as an immune escape strategy in many cancers, including lung cancer. A hi...
Conference Paper
Cancer cells adopt a variety of mechanisms to evade the immune system and avoid T-cell recognition. Disruption of human leukocyte antigen (HLA), which may lead to reduced neoantigen presentation, has been proposed as an immune escape strategy in many cancers, including lung cancer. Mutations in HLA class I genes are infrequent in early stage non-sm...
Data
Table S1. Immune Genes Significantly Differentially Expressed in Lung Adenocarcinomas with HLA LOH versus without HLA LOH, Related to Figure 5
Article
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Background: Intratumoural heterogeneity (ITH) is well recognised in prostate cancer (PC), but its role in high-risk disease is uncertain. A prospective, single-arm, translational study using targeted multiregion prostate biopsies was carried out to study genomic and T-cell ITH in clinically high-risk PC aiming to identify drivers and potential the...
Article
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Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to...
Article
TPS9099 Background: The importance of intratumour heterogeneity (ITH) is increasingly recognised as a driver of cancer progression and survival outcome. However understanding how tumour clonal heterogeneity impacts upon therapeutic outcome is still an area of unmet clinical and scientific need. The TRACERx trial (NCT01888601), a prospective study o...
Article
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The early detection of relapse following primary surgery for non-small cell lung cancer and the characterization of emerging subclones seeding metastatic sites might offer new therapeutic approaches to limit tumor recurrence. The potential to non-invasively track tumor evolutionary dynamics in ctDNA of early-stage lung cancer is not established. He...
Article
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Background Among patients with non–small-cell lung cancer (NSCLC), data on intratumor heterogeneity and cancer genome evolution have been limited to small retrospective cohorts. We wanted to prospectively investigate intratumor heterogeneity in relation to clinical outcome and to determine the clonal nature of driver events and evolutionary process...
Article
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CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-C...
Article
Full-text available
CD25 is expressed at high levels on regulatory T (Treg) cells and was initially proposed as a target for cancer immunotherapy. However, anti-CD25 antibodies have displayed limited activity against established tumors. We demonstrated that CD25 expression is largely restricted to tumor-infiltrating Treg cells in mice and humans. While existing anti-C...
Article
Lung cancer diagnostics have progressed greatly in the previous decade. Development of molecular testing to identify an increasing number of potentially clinically actionable genetic variants, using smaller samples obtained via minimally invasive techniques, is a huge challenge. Tumour heterogeneity and cancer evolution in response to therapy means...
Article
The cellular ancestry of tumor antigens One contributing factor in antitumor immunity is the repertoire of neoantigens created by genetic mutations within tumor cells. Like the corresponding mutations, these neoantigens show intratumoral heterogeneity. Some are present in all tumor cells (clonal), and others are present in only a fraction of cells...
Article
As tumors grow they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intra-tumor heterogeneity (ITH) on anti-tumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantige...
Article
Next-generation sequencing of spatially and temporally separated biopsies and circulating tumor DNA directs therapy in response to tumor evolution and acquired resistance in colorectal cancer. Cancer Discov; 6(2); 122–4. ©2016 AACR. See related article by Russo et al., p. 147.
Article
randomized, placebo-controlled, phase III trial on the use of the anticholinesterasedonepezilforsurvivorsofirradiatedbraintumors.The chronic effects of radiation brain injury are characterized by a diffuse encephalopathy resulting in cognitive impairment. This vascular damage and the loss of neuroglial progenitor cells, particularly in the hippocam...
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Oncolytic vaccinia virus (VV) has shown promise for the delivery of gene therapy and has the potential to be delivered systemically to treat metastatic cancer. VV is known to induce a strong host immune response, which requires immunocompetent models for evaluation. We investigated the systemic delivery of oncolytic vaccinia virus to murine tumours...
Article
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Although we can treat cancers with cytotoxic chemotherapies, target them with molecules that inhibit oncogenic drivers, and induce substantial cell death with radiation, local and metastatic tumours recur, resulting in extensive morbidity and mortality. Indeed, driving a tumour to extinction is difficult. Geographically dispersed species of organis...
Article
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Our knowledge of the morphological heterogeneity of cancer has recently been augmented by the genomic heterogeneity revealed by the use of next-generation sequencing technology. We now know that no two cancers are alike and that even different regions within the same tumour vary in their composition. Tumours consist of multiple clonal populations a...
Article
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The presence of multiple subclones within tumors mandates understanding of longitudinal and spatial subclonal dynamics. Resolving the spatial and temporal heterogeneity of subclones with cancer driver events may offer insight into therapy response, tumor evolutionary histories and clinical trial design.
Article
Pancreatic adenocarcinoma (PDAC) is an aggressive malignancy which is resistant to conventional treatments. PDAC typically contains areas that are profoundly hypoxic which both drives early epithelial to mesenchymal transition, with subsequent metastasis, and is an important determinant of resistance to chemotherapy and radiotherapy. Oncolytic Vacc...
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Purpose The goal of this study was to explore the perspectives and practice of radiation oncologists who treat breast cancer patients who have had breast reconstruction. Methods In 2010, an original electronic survey was sent to all physician members of the American Society of Radiation Oncology, National Cancer Research Institute-Breast Cancer St...
Article
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Vaccinia virus (VV) is an enveloped DNA virus from the poxvirus family and has played a crucial role in the eradication of smallpox. It continues to be used in immunotherapy for the prevention of infectious diseases and treatment of cancer. However, the mechanisms of poxvirus entry, the host factors that affect viral virulence, and the reasons for...
Article
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Selenium is a trace element that is fundamental to human health. Research has mainly focussed on its role in cancer prevention, but recent evidence supports its role in established cancer, with high concentrations inducing tumour cell death and non-toxic concentrations sensitising cells to chemotherapy. However, the precise mechanism of selenium ac...
Article
Background: Serum selenium (Se) concentration at presentation is prognostic of outcome in patients with aggressive B-cell lymphoma (Last et al., JCO, 2003). We have shown that the Se compound MSA enhanced the efficacy of chemotherapeutic agents at non-cytotoxic concentrations in lymphoma cell lines (Juliger et al., Can Res, 2007). Others have repor...
Article
Metastasis accounts for the poor outcome of patients with pancreatic cancer. We recently discovered PRSS3 to be over-expressed in metastatic human pancreatic cancer cells. This study aimed to elucidate the role of PRSS3 in the growth and metastasis of human pancreatic cancer. PRSS3 expression in human pancreatic cancer cell lines was detected by qP...
Conference Paper
Background: Oncolytic virotherapy is a promising approach to treat cancers resistant to conventional therapies. Vaccinia virus, an enveloped DNA virus from the poxvirus family, has been used as a vector for cancer vaccines and oncolytic viral gene therapy. Wild type vaccinia virus has a natural tropism for cancer cells both in vitro and in vivo due...
Article
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Hypoxia contributes to the aggressive and treatment-resistant phenotype of pancreatic ductal adenocarcinoma. Oncolytic vaccinia virus has potential as an anti-tumour agent, but the ability to lyse hypoxic tumour cells is vital for clinical efficacy. We hypothesized that unique aspects of the poxvirus life cycle would protect it from attenuation in...
Article
Changes in delivery must be driven by evidence from ongoing clinical trials The incidence of breast cancer is rising worldwide, particularly in women over 50—it increased by 30-40% between 1973 and 1997.1 In the United States it has decreased by around 10% in line with the reduced use of hormone replacement therapy, but globally the problem is gro...
Article
Vascular endothelial growth factor (VEGF) is an important hypoxia-inducible pro-angiogenic protein that has been linked with an adverse survival outcome after radiotherapy in other cancer types: we hypothesized that this may also occur in prostate cancer. A retrospective study was, therefore, carried out to evaluate the potential of tumor VEGF expr...

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