Publications by authors named "Charles Swanton"

270 Publications

Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma.

Cancer Cell 2021 Nov 28;39(11):1497-1518.e11. Epub 2021 Oct 28.

Department of Cellular Pathology, University College London Hospital, London NW1 2BU, UK.

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8 T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.
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http://dx.doi.org/10.1016/j.ccell.2021.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8599450PMC
November 2021

ctDNA: An emerging neoadjuvant biomarker in resectable solid tumors.

PLoS Med 2021 Oct 12;18(10):e1003771. Epub 2021 Oct 12.

Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, United Kingdom.

Christopher Abbosh and Charles Swanton discuss circulating tumor DNA as a potential biomarker for neoadjuvant treatment response in solid tumors.
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http://dx.doi.org/10.1371/journal.pmed.1003771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509880PMC
October 2021

Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry.

Nat Commun 2021 10 8;12(1):5906. Epub 2021 Oct 8.

Oncogene Biology Laboratory, The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.

Mouse models are critical in pre-clinical studies of cancer therapy, allowing dissection of mechanisms through chemical and genetic manipulations that are not feasible in the clinical setting. In studies of the tumour microenvironment (TME), multiplexed imaging methods can provide a rich source of information. However, the application of such technologies in mouse tissues is still in its infancy. Here we present a workflow for studying the TME using imaging mass cytometry with a panel of 27 antibodies on frozen mouse tissues. We optimise and validate image segmentation strategies and automate the process in a Nextflow-based pipeline (imcyto) that is scalable and portable, allowing for parallelised segmentation of large multi-image datasets. With these methods we interrogate the remodelling of the TME induced by a KRAS G12C inhibitor in an immune competent mouse orthotopic lung cancer model, highlighting the infiltration and activation of antigen presenting cells and effector cells.
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http://dx.doi.org/10.1038/s41467-021-26214-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501076PMC
October 2021

Functional antibody and T-cell immunity following SARS-CoV-2 infection, including by variants of concern, in patients with cancer: the CAPTURE study.

Res Sq 2021 Sep 20. Epub 2021 Sep 20.

Patients with cancer have higher COVID-19 morbidity and mortality. Here we present the prospective CAPTURE study (NCT03226886) integrating longitudinal immune profiling with clinical annotation. Of 357 patients with cancer, 118 were SARS-CoV-2-positive, 94 were symptomatic and 2 patients died of COVID-19. In this cohort, 83% patients had S1-reactive antibodies, 82% had neutralizing antibodies against WT, whereas neutralizing antibody titers (NAbT) against the Alpha, Beta, and Delta variants were substantially reduced. Whereas S1-reactive antibody levels decreased in 13% of patients, NAbT remained stable up to 329 days. Patients also had detectable SARS-CoV-2-specific T cells and CD4+ responses correlating with S1-reactive antibody levels, although patients with hematological malignancies had impaired immune responses that were disease and treatment-specific, but presented compensatory cellular responses, further supported by clinical. Overall, these findings advance the understanding of the nature and duration of immune response to SARS-CoV-2 in patients with cancer.
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http://dx.doi.org/10.21203/rs.3.rs-916427/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475970PMC
September 2021

9p21 loss confers a cold tumor immune microenvironment and primary resistance to immune checkpoint therapy.

Nat Commun 2021 09 23;12(1):5606. Epub 2021 Sep 23.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Immune checkpoint therapy (ICT) provides substantial clinical benefits to cancer patients, but a large proportion of cancers do not respond to ICT. To date, the genomic underpinnings of primary resistance to ICT remain elusive. Here, we performed immunogenomic analysis of data from TCGA and clinical trials of anti-PD-1/PD-L1 therapy, with a particular focus on homozygous deletion of 9p21.3 (9p21 loss), one of the most frequent genomic defects occurring in ~13% of all cancers. We demonstrate that 9p21 loss confers "cold" tumor-immune phenotypes, characterized by reduced abundance of tumor-infiltrating leukocytes (TILs), particularly, T/B/NK cells, altered spatial TILs patterns, diminished immune cell trafficking/activation, decreased rate of PD-L1 positivity, along with activation of immunosuppressive signaling. Notably, patients with 9p21 loss exhibited significantly lower response rates to ICT and worse outcomes, which were corroborated in eight ICT trials of >1,000 patients. Further, 9p21 loss synergizes with PD-L1/TMB for patient stratification. A "response score" was derived by incorporating 9p21 loss, PD-L1 expression and TMB levels in pre-treatment tumors, which outperforms PD-L1, TMB, and their combination in identifying patients with high likelihood of achieving sustained response from otherwise non-responders. Moreover, we describe potential druggable targets in 9p21-loss tumors, which could be exploited to design rational therapeutic interventions.
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http://dx.doi.org/10.1038/s41467-021-25894-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8460828PMC
September 2021

Using DNA sequencing data to quantify T cell fraction and therapy response.

Nature 2021 Sep 8;597(7877):555-560. Epub 2021 Sep 8.

Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.

The immune microenvironment influences tumour evolution and can be both prognostic and predict response to immunotherapy. 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 actionable mutations. Here we develop T cell exome TREC tool (T cell ExTRECT), a method for estimation of T cell fraction from WES samples using a signal from T cell receptor excision circle (TREC) loss during V(D)J recombination of the T cell receptor-α gene (TCRA (also known as TRA)). TCRA T cell fraction correlates with orthogonal TIL estimates and is agnostic to sample type. Blood TCRA T cell fraction is higher in females than in males and correlates with both tumour immune infiltrate and presence of bacterial sequencing reads. Tumour TCRA T cell fraction is prognostic in lung adenocarcinoma. Using a meta-analysis of tumours treated with immunotherapy, we show that tumour TCRA T cell fraction predicts immunotherapy response, providing value beyond measuring tumour mutational burden. Applying T cell ExTRECT to a multi-sample pan-cancer cohort reveals a high diversity of the degree of immune infiltration within tumours. Subclonal loss of 12q24.31-32, encompassing SPPL3, is associated with reduced TCRA T cell fraction. T cell ExTRECT provides a cost-effective technique to characterize immune infiltrate alongside somatic changes.
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http://dx.doi.org/10.1038/s41586-021-03894-5DOI Listing
September 2021

Cancer evolution: Darwin and beyond.

EMBO J 2021 09 30;40(18):e108389. Epub 2021 Aug 30.

Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.

Clinical and laboratory studies over recent decades have established branched evolution as a feature of cancer. However, while grounded in somatic selection, several lines of evidence suggest a Darwinian model alone is insufficient to fully explain cancer evolution. First, the role of macroevolutionary events in tumour initiation and progression contradicts Darwin's central thesis of gradualism. Whole-genome doubling, chromosomal chromoplexy and chromothripsis represent examples of single catastrophic events which can drive tumour evolution. Second, neutral evolution can play a role in some tumours, indicating that selection is not always driving evolution. Third, increasing appreciation of the role of the ageing soma has led to recent generalised theories of age-dependent carcinogenesis. Here, we review these concepts and others, which collectively argue for a model of cancer evolution which extends beyond Darwin. We also highlight clinical opportunities which can be grasped through targeting cancer vulnerabilities arising from non-Darwinian patterns of evolution.
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http://dx.doi.org/10.15252/embj.2021108389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8441388PMC
September 2021

Capturing cancer evolution using genetically engineered mouse models (GEMMs).

Trends Cell Biol 2021 Dec 13;31(12):1007-1018. Epub 2021 Aug 13.

Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; University College London Hospitals NHS Trust, London, UK. Electronic address:

Initiating from a single cell, cancer undergoes clonal evolution, leading to a high degree of intratumor heterogeneity (ITH). The arising genetic heterogeneity between cancer cells is influenced by exogenous and endogenous forces that shape the composition of clones within tumors. Preclinical mouse models have provided a valuable tool for understanding cancer, helping to build a fundamental understanding of tumor initiation, progression, and metastasis. Until recently, genetically engineered mouse models (GEMMS) of cancer had lacked the genetic diversity found in human tumors, in which evolution may be driven by long-term carcinogen exposure and DNA damage. However, advances in sequencing technology and in our understanding of the drivers of genetic instability have given us the knowledge to generate new mouse models, offering an approach to functionally explore mechanisms of tumor evolution.
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http://dx.doi.org/10.1016/j.tcb.2021.07.003DOI Listing
December 2021

Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study.

Lancet Oncol 2021 09 30;22(9):1290-1300. Epub 2021 Jul 30.

Sarah Cannon Research Institute, Nashville, TN, USA; Tennessee Oncology, Nashville, TN, USA.

Background: Systemic therapies for metastatic biliary tract cancers are few, and patients have a median overall survival of less than 1 year. MyPathway evaluates the activity of US Food and Drug Administration-approved therapies in non-indicated tumours with potentially actionable molecular alterations. In this study, we present an analysis of patients with metastatic biliary tract cancers with HER2 amplification, overexpression, or both treated with a dual anti-HER2 regimen, pertuzumab plus trastuzumab, from MyPathway.

Methods: MyPathway is a non-randomised, multicentre, open-label, phase 2a, multiple basket study. Patients aged 18 years and older with previously treated metastatic biliary tract cancers with HER2 amplification, HER2 overexpression, or both and an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled from 23 study sites in the USA and received intravenous pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) plus trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks). The primary endpoint was investigator-assessed objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. The primary outcome and adverse events were analysed in all patients who received at least one dose of pertuzumab and trastuzumab. This trial is registered with ClinicalTrials.gov, NCT02091141, and is ongoing.

Findings: 39 patients enrolled in the MyPathway HER2 biliary tract cancer cohort between Oct 28, 2014, and May 29, 2019, were evaluable for anti-tumour activity by the March 10, 2020, data cutoff date. Median follow-up was 8·1 months (IQR 2·7-15·7). Nine of 39 patients achieved a partial response (objective response rate 23% [95% CI 11-39]). Grade 3-4 treatment-emergent adverse events were reported in 18 (46%) of 39 patients, most commonly increased alanine aminotransferase and increased aspartate aminotransferase (each five [13%] of 39). Treatment-related grade 3 adverse events were reported in three (8%) of 39 patients, including increased alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, and blood bilirubin. Serious treatment-emergent adverse events were observed in ten (26%) of 39 patients, of which only abdominal pain occurred in more than one patient (two [5%] of 39). There were no treatment-related serious adverse events, treatment-related grade 4 events, or deaths.

Interpretation: Treatment was well tolerated in patients with previously treated HER2-positive metastatic biliary tract cancer. The response rate is promising for the initiation of randomised, controlled trials of pertuzumab plus trastuzumab in this patient population.

Funding: F Hoffmann-La Roche-Genentech.
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http://dx.doi.org/10.1016/S1470-2045(21)00336-3DOI Listing
September 2021

Misuse of SARS-CoV-2 testing in symptomatic health-care staff in the UK - Authors' reply.

Lancet 2020 10;396(10259):1329-1330

Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK; Cancer Evolution and Genome Instability Laboratory, Francis Crick Institute, London NW1 1AT, UK; University College London Hospitals NHS Trust, London, UK. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(20)32145-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581353PMC
October 2020

Reduced antibody cross-reactivity following infection with B.1.1.7 than with parental SARS-CoV-2 strains.

Elife 2021 07 29;10. Epub 2021 Jul 29.

Retroviral Immunology, London, United Kingdom.

Background: The degree of heterotypic immunity induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains is a major determinant of the spread of emerging variants and the success of vaccination campaigns, but remains incompletely understood.

Methods: We examined the immunogenicity of SARS-CoV-2 variant B.1.1.7 (Alpha) that arose in the United Kingdom and spread globally. We determined titres of spike glycoprotein-binding antibodies and authentic virus neutralising antibodies induced by B.1.1.7 infection to infer homotypic and heterotypic immunity.

Results: Antibodies elicited by B.1.1.7 infection exhibited significantly reduced recognition and neutralisation of parental strains or of the South Africa variant B.1.351 (Beta) than of the infecting variant. The drop in cross-reactivity was significantly more pronounced following B.1.1.7 than parental strain infection.

Conclusions: The results indicate that heterotypic immunity induced by SARS-CoV-2 variants is asymmetric.

Funding: This work was supported by the Francis Crick Institute and the Max Planck Institute for Dynamics of Complex Technical Systems, Magdeburg.
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http://dx.doi.org/10.7554/eLife.69317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352583PMC
July 2021

Liquid Biopsy for Advanced NSCLC: A Consensus Statement From the International Association for the Study of Lung Cancer.

J Thorac Oncol 2021 10 8;16(10):1647-1662. Epub 2021 Jul 8.

Division of Hematology/Oncology, UC Davis Comprehensive Cancer Center, Sacramento, California. Electronic address:

Although precision medicine has had a mixed impact on the clinical management of patients with advanced-stage cancer overall, for NSCLC, and more specifically for lung adenocarcinoma, the advances have been dramatic, largely owing to the genomic complexity and growing number of druggable oncogene drivers. Furthermore, although tumor tissue is historically the "accepted standard" biospecimen for these molecular analyses, there are considerable innate limitations. Thus, liquid biopsy represents a practical alternative source for investigating tumor-derived somatic alterations. Although data are most robust in NSCLC, patients with other cancer types may also benefit from this minimally invasive approach to facilitate selection of targeted therapies. The liquid biopsy approach includes a variety of methodologies for circulating analytes. From a clinical point of view, plasma circulating tumor DNA is the most extensively studied and widely adopted alternative to tissue tumor genotyping in solid tumors, including NSCLC, first entering clinical practice for detection of EGFR mutations in NSCLC. Since the publication of the first International Association for the Study of Lung Cancer (IASLC) liquid biopsy statement in 2018, several additional advances have been made in this field, leading to changes in the therapeutic decision-making algorithm for advanced NSCLC and prompting this 2021 update. In view of the novel and impressive technological advances made in the past few years, the growing clinical application of plasma-based, next-generation sequencing, and the recent Food and Drug and Administration approval in the United States of two different assays for circulating tumor DNA analysis, IASLC revisited the role of liquid biopsy in therapeutic decision-making in a recent workshop in October 2020 and the question of "plasma first" versus "tissue first" approach toward molecular testing for advanced NSCLC. Moreover, evidence-based recommendations from IASLC provide an international perspective on when to order which test and how to interpret the results. Here, we present updates and additional considerations to the previous statement article as a consensus from a multidisciplinary and international team of experts selected by IASLC.
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http://dx.doi.org/10.1016/j.jtho.2021.06.017DOI Listing
October 2021

Immunogenomics of Colorectal Cancer Response to Checkpoint Blockade: Analysis of the KEYNOTE 177 Trial and Validation Cohorts.

Gastroenterology 2021 Oct 29;161(4):1179-1193. Epub 2021 Jun 29.

Cancer Systems Biology Laboratory, The Francis Crick Institute, London, United Kingdom; School of Cancer and Pharmaceutical Sciences, King's College London, London, United Kingdom. Electronic address:

Background & Aims: Colorectal cancer (CRC) shows variable response to immune checkpoint blockade, which can only partially be explained by high tumor mutational burden (TMB). We conducted an integrated study of the cancer tissue and associated tumor microenvironment (TME) from patients treated with pembrolizumab (KEYNOTE 177 clinical trial) or nivolumab to dissect the cellular and molecular determinants of response to anti- programmed cell death 1 (PD1) immunotherapy.

Methods: We selected multiple regions per tumor showing variable T-cell infiltration for a total of 738 regions from 29 patients, divided into discovery and validation cohorts. We performed multiregional whole-exome and RNA sequencing of the tumor cells and integrated these with T-cell receptor sequencing, high-dimensional imaging mass cytometry, detection of programmed death-ligand 1 (PDL1) interaction in situ, multiplexed immunofluorescence, and computational spatial analysis of the TME.

Results: In hypermutated CRCs, response to anti-PD1 immunotherapy was not associated with TMB but with high clonality of immunogenic mutations, clonally expanded T cells, low activation of Wnt signaling, deregulation of the interferon gamma pathway, and active immune escape mechanisms. Responsive hypermutated CRCs were also rich in cytotoxic and proliferating PD1CD8 T cells interacting with PDL1 antigen-presenting macrophages.

Conclusions: Our study clarified the limits of TMB as a predictor of response of CRC to anti-PD1 immunotherapy. It identified a population of antigen-presenting macrophages interacting with CD8 T cells that consistently segregate with response. We therefore concluded that anti-PD1 agents release the PD1-PDL1 interaction between CD8 T cells and macrophages to promote cytotoxic antitumor activity.
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http://dx.doi.org/10.1053/j.gastro.2021.06.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8527923PMC
October 2021

E3 ubiquitin ligase HECTD2 mediates melanoma progression and immune evasion.

Oncogene 2021 Sep 18;40(37):5567-5578. Epub 2021 Jun 18.

Retroviral Immunology Laboratory, The Francis Crick Institute, London, UK.

The ubiquitin-proteasome system maintains protein homoeostasis, underpins the cell cycle, and is dysregulated in cancer. However, the role of individual E3 ubiquitin ligases, which mediate the final step in ubiquitin-mediated proteolysis, remains incompletely understood. Identified through screening for cancer-specific endogenous retroviral transcripts, we show that the little-studied E3 ubiquitin ligase HECTD2 exerts dominant control of tumour progression in melanoma. HECTD2 cell autonomously drives the proliferation of human and murine melanoma cells by accelerating the cell cycle. HECTD2 additionally regulates cancer cell production of immune mediators, initiating multiple immune suppressive pathways, which include the cyclooxygenase 2 (COX2) pathway. Accordingly, higher HECTD2 expression is associated with weaker anti-tumour immunity and unfavourable outcome of PD-1 blockade in human melanoma and counteracts immunity against a model tumour antigen in murine melanoma. This central, multifaceted role of HECTD2 in cancer cell-autonomous proliferation and in immune evasion may provide a single target for a multipronged therapy of melanoma.
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http://dx.doi.org/10.1038/s41388-021-01885-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8445817PMC
September 2021

SARS-CoV-2 detection by a clinical diagnostic RT-LAMP assay.

Wellcome Open Res 2021 21;6. Epub 2021 May 21.

The Francis Crick Institute, London, NW1 1AT, UK.

The ongoing pandemic of SARS-CoV-2 calls for rapid and cost-effective methods to accurately identify infected individuals. The vast majority of patient samples is assessed for viral RNA presence by RT-qPCR. Our biomedical research institute, in collaboration between partner hospitals and an accredited clinical diagnostic laboratory, established a diagnostic testing pipeline that has reported on more than 252,000 RT-qPCR results since its commencement at the beginning of April 2020. However, due to ongoing demand and competition for critical resources, alternative testing strategies were sought. In this work, we present a clinically-validated procedure for high-throughput SARS-CoV-2 detection by RT-LAMP that is robust, reliable, repeatable, specific, and inexpensive.
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http://dx.doi.org/10.12688/wellcomeopenres.16517.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170534PMC
May 2021

Cytokine release syndrome in a patient with colorectal cancer after vaccination with BNT162b2.

Nat Med 2021 08 26;27(8):1362-1366. Epub 2021 May 26.

Gastrointestinal and Lymphoma Unit, The Royal Marsden NHS Foundation Trust, Sutton, UK.

Patients with cancer are currently prioritized in coronavirus disease 2019 (COVID-19) vaccination programs globally, which includes administration of mRNA vaccines. Cytokine release syndrome (CRS) has not been reported with mRNA vaccines and is an extremely rare immune-related adverse event of immune checkpoint inhibitors. We present a case of CRS that occurred 5 d after vaccination with BTN162b2 (tozinameran)-the Pfizer-BioNTech mRNA COVID-19 vaccine-in a patient with colorectal cancer on long-standing anti-PD-1 monotherapy. The CRS was evidenced by raised inflammatory markers, thrombocytopenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness. The close temporal association of vaccination and diagnosis of CRS in this case suggests that CRS was a vaccine-related adverse event; with anti-PD1 blockade as a potential contributor. Overall, further prospective pharmacovigillence data are needed in patients with cancer, but the benefit-risk profile remains strongly in favor of COVID-19 vaccination in this population.
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http://dx.doi.org/10.1038/s41591-021-01387-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8363501PMC
August 2021

Sex-Based Dimorphism of Anticancer Immune Response and Molecular Mechanisms of Immune Evasion.

Clin Cancer Res 2021 Aug 20;27(15):4311-4324. Epub 2021 May 20.

Department of Oncology, Weill Cornel Medicine, New York, New York.

Purpose: We previously demonstrated that sex influences response to immune checkpoint inhibitors. In this article, we investigate sex-based differences in the molecular mechanisms of anticancer immune response and immune evasion in patients with NSCLC.

Experimental Design: We analyzed (i) transcriptome data of 2,575 early-stage NSCLCs from seven different datasets; (ii) 327 tumor samples extensively characterized at the molecular level from the TRACERx lung study; (iii) two independent cohorts of 329 and 391 patients, respectively, with advanced NSCLC treated with anti-PD-1/anti-PD-L1 drugs.

Results: As compared with men, the tumor microenvironment (TME) of women was significantly enriched for a number of innate and adaptive immune cell types, including specific T-cell subpopulations. NSCLCs of men and women exploited different mechanisms of immune evasion. The TME of females was characterized by significantly greater T-cell dysfunction status, higher expression of inhibitory immune checkpoint molecules, and higher abundance of immune-suppressive cells, including cancer-associated fibroblasts, MDSCs, and regulatory T cells. In contrast, the TME of males was significantly enriched for a T-cell-excluded phenotype. We reported data supporting impaired neoantigens presentation to immune system in tumors of men, as molecular mechanism explaining the findings observed. Finally, in line with our results, we showed significant sex-based differences in the association between TMB and outcome of patients with advanced NSCLC treated with anti-PD-1/PD-L1 drugs.

Conclusions: We demonstrated meaningful sex-based differences of anticancer immune response and immune evasion mechanisms, that may be exploited to improve immunotherapy efficacy for both women and men.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611463PMC
August 2021

Selection of metastasis competent subclones in the tumour interior.

Nat Ecol Evol 2021 07 17;5(7):1033-1045. Epub 2021 May 17.

Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.

The genetic evolutionary features of solid tumour growth are becoming increasingly well described, but the spatial and physical nature of subclonal growth remains unclear. Here, we utilize 102 macroscopic whole-tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilizing a digital image processing pipeline, a renal pathologist marked the boundaries between tumour and normal tissue and extracted positions of boundary line and biopsy regions to X and Y coordinates. We then integrated coordinates with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing subclones preferentially originate from the tumour centre. Collectively, these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading to a greater opportunity for driver somatic copy number alterations to arise and expand due to selective advantage. Tumour subclone growth is predominantly spatially contiguous in nature. We found only two cases of subclone dispersal, one of which was associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting that a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution.
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http://dx.doi.org/10.1038/s41559-021-01456-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611703PMC
July 2021

Induction of APOBEC3 Exacerbates DNA Replication Stress and Chromosomal Instability in Early Breast and Lung Cancer Evolution.

Cancer Discov 2021 Oct 4;11(10):2456-2473. Epub 2021 May 4.

DSB Repair Metabolism Laboratory, The Francis Crick Institute, London, United Kingdom.

APOBEC3 enzymes are cytosine deaminases implicated in cancer. Precisely when expression is induced during cancer development remains to be defined. Here we show that specific genes are upregulated in breast ductal carcinoma , and in preinvasive lung cancer lesions coincident with cellular proliferation. We observe evidence of APOBEC3-mediated subclonal mutagenesis propagated from TRACERx preinvasive to invasive non-small cell lung cancer (NSCLC) lesions. We find that APOBEC3B exacerbates DNA replication stress and chromosomal instability through incomplete replication of genomic DNA, manifested by accumulation of mitotic ultrafine bridges and 53BP1 nuclear bodies in the G phase of the cell cycle. Analysis of TRACERx NSCLC clinical samples and mouse lung cancer models revealed expression driving replication stress and chromosome missegregation. We propose that APOBEC3 is functionally implicated in the onset of chromosomal instability and somatic mutational heterogeneity in preinvasive disease, providing fuel for selection early in cancer evolution. SIGNIFICANCE: This study reveals the dynamics and drivers of gene expression in preinvasive disease and the exacerbation of cellular diversity by APOBEC3B through DNA replication stress to promote chromosomal instability early in cancer evolution..
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http://dx.doi.org/10.1158/2159-8290.CD-20-0725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487921PMC
October 2021

Melanoma dedifferentiation induced by IFN-γ epigenetic remodeling in response to anti-PD-1 therapy.

J Clin Invest 2021 06;131(12)

Department of Medicine.

Melanoma dedifferentiation has been reported to be a state of cellular resistance to targeted therapies and immunotherapies as cancer cells revert to a more primitive cellular phenotype. Here, we show that, counterintuitively, the biopsies of patient tumors that responded to anti-programmed cell death 1 (anti-PD-1) therapy had decreased expression of melanocytic markers and increased neural crest markers, suggesting treatment-induced dedifferentiation. When modeling the effects in vitro, we documented that melanoma cell lines that were originally differentiated underwent a process of neural crest dedifferentiation when continuously exposed to IFN-γ, through global chromatin landscape changes that led to enrichment in specific hyperaccessible chromatin regions. The IFN-γ-induced dedifferentiation signature corresponded with improved outcomes in patients with melanoma, challenging the notion that neural crest dedifferentiation is entirely an adverse phenotype.
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http://dx.doi.org/10.1172/JCI145859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203459PMC
June 2021

AMBRA1 regulates cyclin D to guard S-phase entry and genomic integrity.

Nature 2021 Apr 14;592(7856):799-803. Epub 2021 Apr 14.

Department of Pediatric Onco-Hematology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

Mammalian development, adult tissue homeostasis and the avoidance of severe diseases including cancer require a properly orchestrated cell cycle, as well as error-free genome maintenance. The key cell-fate decision to replicate the genome is controlled by two major signalling pathways that act in parallel-the MYC pathway and the cyclin D-cyclin-dependent kinase (CDK)-retinoblastoma protein (RB) pathway. Both MYC and the cyclin D-CDK-RB axis are commonly deregulated in cancer, and this is associated with increased genomic instability. The autophagic tumour-suppressor protein AMBRA1 has been linked to the control of cell proliferation, but the underlying molecular mechanisms remain poorly understood. Here we show that AMBRA1 is an upstream master regulator of the transition from G1 to S phase and thereby prevents replication stress. Using a combination of cell and molecular approaches and in vivo models, we reveal that AMBRA1 regulates the abundance of D-type cyclins by mediating their degradation. Furthermore, by controlling the transition from G1 to S phase, AMBRA1 helps to maintain genomic integrity during DNA replication, which counteracts developmental abnormalities and tumour growth. Finally, we identify the CHK1 kinase as a potential therapeutic target in AMBRA1-deficient tumours. These results advance our understanding of the control of replication-phase entry and genomic integrity, and identify the AMBRA1-cyclin D pathway as a crucial cell-cycle-regulatory mechanism that is deeply interconnected with genomic stability in embryonic development and tumorigenesis.
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http://dx.doi.org/10.1038/s41586-021-03422-5DOI Listing
April 2021

Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes.

Cell 2021 04 7;184(8):2239-2254.e39. Epub 2021 Apr 7.

Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK.

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.
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http://dx.doi.org/10.1016/j.cell.2021.03.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054914PMC
April 2021

Tracking Cancer Evolution through the Disease Course.

Cancer Discov 2021 04;11(4):916-932

Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.

During cancer evolution, constituent tumor cells compete under dynamic selection pressures. Phenotypic variation can be observed as intratumor heterogeneity, which is propagated by genome instability leading to mutations, somatic copy-number alterations, and epigenomic changes. TRACERx was set up in 2014 to observe the relationship between intratumor heterogeneity and patient outcome. By integrating multiregion sequencing of primary tumors with longitudinal sampling of a prospectively recruited patient cohort, cancer evolution can be tracked from early- to late-stage disease and through therapy. Here we review some of the key features of the studies and look to the future of the field. SIGNIFICANCE: Cancers evolve and adapt to environmental challenges such as immune surveillance and treatment pressures. The TRACERx studies track cancer evolution in a clinical setting, through primary disease to recurrence. Through multiregion and longitudinal sampling, evolutionary processes have been detailed in the tumor and the immune microenvironment in non-small cell lung cancer and clear-cell renal cell carcinoma. TRACERx has revealed the potential therapeutic utility of targeting clonal neoantigens and ctDNA detection in the adjuvant setting as a minimal residual disease detection tool primed for translation into clinical trials.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611362PMC
April 2021

Clonal architecture in mesothelioma is prognostic and shapes the tumour microenvironment.

Nat Commun 2021 03 19;12(1):1751. Epub 2021 Mar 19.

The Francis Crick Institute, London, UK.

Malignant Pleural Mesothelioma (MPM) is typically diagnosed 20-50 years after exposure to asbestos and evolves along an unknown evolutionary trajectory. To elucidate this path, we conducted multi-regional exome sequencing of 90 tumour samples from 22 MPMs acquired at surgery. Here we show that exomic intratumour heterogeneity varies widely across the cohort. Phylogenetic tree topology ranges from linear to highly branched, reflecting a steep gradient of genomic instability. Using transfer learning, we detect repeated evolution, resolving 5 clusters that are prognostic, with temporally ordered clonal drivers. BAP1/-3p21 and FBXW7/-chr4 events are always early clonal. In contrast, NF2/-22q events, leading to Hippo pathway inactivation are predominantly late clonal, positively selected, and when subclonal, exhibit parallel evolution indicating an evolutionary constraint. Very late somatic alteration of NF2/22q occurred in one patient 12 years after surgery. Clonal architecture and evolutionary clusters dictate MPM inflammation and immune evasion. These results reveal potentially drugable evolutionary bottlenecking in MPM, and an impact of clonal architecture on shaping the immune landscape, with potential to dictate the clinical response to immune checkpoint inhibition.
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http://dx.doi.org/10.1038/s41467-021-21798-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979861PMC
March 2021

Impact of cancer evolution on immune surveillance and checkpoint inhibitor response.

Semin Cancer Biol 2021 Feb 22. Epub 2021 Feb 22.

Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, NW1 1AT, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, London, WC1E 6DD, UK. Electronic address:

Intratumour heterogeneity (ITH) is pervasive across all cancers studied and may provide the evolving tumour multiple routes to escape immune surveillance. Immune checkpoint inhibitors (CPIs) are rapidly becoming standard of care for many cancers. Here, we discuss recent work investigating the influence of ITH on patient response to immune checkpoint inhibitor (CPI) therapy. At its simplest, ITH may confound the diagnostic accuracy of predictive biomarkers used to stratify patients for CPI therapy. Furthermore, ITH is fuelled by mechanisms of genetic instability that can both engage immune surveillance and drive immune evasion. A greater appreciation of the interplay between ITH and the immune system may hold the key to increasing the proportion of patients experiencing durable responses from CPI therapy.
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http://dx.doi.org/10.1016/j.semcancer.2021.02.013DOI Listing
February 2021

Understanding the impact of immune-mediated selection on lung cancer evolution.

Br J Cancer 2021 May 24;124(10):1615-1617. Epub 2021 Feb 24.

Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.

Understanding how a tumour evolves and avoids immune recognition is paramount to improving cancer immunotherapy and patient outcome. Here we examine our recent integration of multi-region genomic, transcriptomic, epigenomic, pathology, and clinical data, highlight the need for a systematic examination of immune escape mechanisms, and discuss implications for immunotherapy approaches.
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http://dx.doi.org/10.1038/s41416-020-01232-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110793PMC
May 2021
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