20 research outputs found
Attending community-based lung cancer screening influences smoking behaviour in deprived populations
No full textObjectives: The impact of lung cancer screening on smoking is unclear, especially in deprived populations who are underrepresented in screening trials. The aim of this observational cohort study was to investigate whether a community-based lung cancer screening programme influenced smoking behaviour and smoking attitude in socio-economically deprived populations. Material and Methods: Ever-smokers, age 55–74, registered at participating General Practices were invited to a community-based Lung Health Check (LHC). This included an assessment of respiratory symptoms, lung cancer risk (PLCOm2012), spirometry and signposting to stop smoking services. Those at high risk (PLCOM2012≥1.51%) were offered annual low-dose CT screening over two rounds. Self-reported smoking status and behaviour were recorded at the LHC and again 12 months later, when attitudes to smoking were also assessed. Results: 919 participants (51% women) were included in the analysis (77% of attendees); median deprivation rank in the lowest decile for England. At baseline 50.3% were current smokers. One-year quit rate was 10.2%, quitting was associated with increased baseline symptoms (adjOR 2.62, 95% CI 1.07–6.41; p = 0.035) but not demographics or screening results. 55% attributed quitting to the LHC. In current smokers, 44% reported the LHC had made them consider stopping, 29% it made them try to stop and 25% made them smoke less whilst only 1.7% and 0.7% said it made them worry less about smoking or think it acceptable to smoke. Conclusions: Our data suggest a community-based lung cancer screening programme in deprived areas positively impacts smoking behaviour, with no evidence of a ‘licence to smoke’ in those screened.</p
MHC Hammer reveals genetic and non-genetic HLA disruption in cancer evolution
No full textDisruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% and 15% of LUAD, LUSC and ER+ cancers. Consistent with the importance of HLA dysfunction in tumor evolution, in LUADs, HLA LOH was associated with metastasis and LUAD primary tumor regions seeding a metastasis had a lower effective neoantigen burden than non-seeding regions. These data highlight the extent and importance of HLA transcriptomic disruption, including repression and alternative splicing in cancer evolution
Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution
No full textImmune 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 determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens
Neoantigen-directed immune escape in lung cancer evolution
No full textThe 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 mechanisms of neoantigen presentation dysfunction enriched in distinct immune microenvironments. Sparsely infiltrated tumours exhibited a waning of neoantigen editing during tumour evolution, indicative of historical immune editing, or copy-number loss of previously clonal neoantigens. Immune-infiltrated tumour regions exhibited ongoing immunoediting, with either loss of heterozygosity in human leukocyte antigens or depletion of expressed neoantigens. We identified promoter hypermethylation of genes that contain neoantigenic mutations as an epigenetic mechanism of immunoediting. Our results suggest that the immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion, which are clinically relevant and forecast poor disease-free survival.sponsorship: We thank the members of the TRACERx consortium for participating in this study. C.S. is Royal Society Napier Research Professor. C.S. is supported by the Francis Crick Institute, which receives its core funding from the Medical Research Council (FC001169), the Wellcome Trust (FC001169), and Cancer Research UK (FC001169). C.S. is funded by Cancer Research UK (TRACERx and CRUK Cancer Immunotherapy Catalyst Network), the CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), the Rosetrees and Stoneygate Trusts, NovoNordisk Foundation (ID 16584), the Breast Cancer Research Foundation (BCRF), the European Research Council Consolidator Grant (FP7-THESEUS-617844), European Commission ITN (FP7-PloidyNet-607722), Chromavision (this project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 665233), National Institute for Health Research (NIHR), the University College London Hospitals Biomedical Research Centre (BRC) and the Cancer Research UK University College London Experimental Cancer Medicine Centre. N.M. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (211179/Z/18/Z), and also receives funding from CRUK Lung Cancer Centre of Excellence, Rosetrees and the University College London Hospitals Biomedical Research Centre (BRC) and the Cancer Research UK University College London Experimental Cancer Medicine Centre. E.L.C., J.D. and P.V.L. are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202), and the Wellcome Trust (FC001202). P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation's support towards the establishment of The Francis Crick Institute. J.D. is a postdoctoral fellow of the Research Foundation -Flanders (FWO). S.A.Q. is funded by a CRUK Senior Cancer Research Fellowship (C36463/A22246), a CRUK Biotherapeutic Program Grant (C36463/A20764), the Cancer Immunotherapy Accelerator Award (CITA-CRUK) (C33499/A20265) and Rosetrees. M.T. received funding from the People Programme Marie Curie Actions (FP7/2007-2013/WHRI-ACADEMY-608765) and the Danish Council for Strategic Research (1309-00006B). The TRACERx study (Clinicaltrials. gov no: NCT01888601) is sponsored by University College London (UCL/12/0279) and has been approved by an independent Research Ethics Committee (13/LO/1546). TRACERx is funded by Cancer Research UK (C11496/A17786) and coordinated through the Cancer Research UK and UCL Cancer Trials Centre. For the RRBS methylation data, we acknowledge technical support from the CRUK-UCL Centre-funded Genomics and Genome Engineering Core Facility of the UCL Cancer Institute and grant support from the NIHR BRC (BRC275/CN/SB/101330). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. The results published here are based in part upon data generated by The Cancer Genome Atlas pilot project established by the NCI and the National Human Genome Research Institute. The data were retrieved through database of Genotypes and Phenotypes (dbGaP) authorization (accession number phs000178.v9.p8). Information about TCGA and the constituent investigators and institutions the TCGA research network can be found at http://cancergenome.nih.gov/. (Francis Crick Institute - Medical Research Council|FC001169, Wellcome Trust|FC001169, Wellcome Trust|211179/Z/18/Z, Wellcome Trust|FC001202, Cancer Research UK|FC001169, Cancer Research UK|C11496/A17786, Cancer Research UK (TRACERx), CRUK Lung Cancer Centre of Excellence, Stand Up 2 Cancer (SU2C), Rosetrees Trust, Stoneygate Trust, NovoNordisk Foundation|16584, Breast Cancer Research Foundation (BCRF), European Research Council Consolidator Grant|FP7-THESEUS-617844, European Commission ITN|FP7-PloidyNet-607722, Chromavision (European Union's Horizon 2020 research and innovation programme)|665233, National Institute for Health Research (NIHR), University College London Hospitals Biomedical Research Centre (BRC), Cancer Research UK University College London Experimental Cancer Medicine Centre, Royal Society|211179/Z/18/Z, Rosetrees, Francis Crick Institute - Cancer Research UK|FC001202, UK Medical Research Council|FC001202, Winton Charitable Foundation, CRUK Senior Cancer Research Fellowship|C36463/A22246, CRUK Biotherapeutic Program Grant|C36463/A20764, Cancer Immunotherapy Accelerator Award (CITA-CRUK)|C33499/A20265, People Programme Marie Curie Actions|FP7/2007-2013/WHRI-ACADEMY-608765, Danish Council for Strategic Research|1309-00006B, University College London|UCL/12/0279, CRUK-UCL Centre, NIHR BRC|BRC275/CN/SB/101330, Cancer Research UK (CRUK Cancer Immunotherapy Catalyst Network), Cancer Research UK|23896, Cancer Research UK|19278, Cancer Research UK|24314, Cancer Research UK|20466, Cancer Research UK|28990, Cancer Research UK|20764, Cancer Research UK|16463, Cancer Research UK|20465, Cancer Research UK|17786, Cancer Research UK|21999, Cancer Research UK|24956, Cancer Research UK; Versus Arthritis|22246, Cancer Research UK; Versus Arthritis|20265, Medical Research Council|MC_UP_1203/1, National Institute for Health Research|CL-2015-18-009, National Institute for Health Research|CL-2015-17-002, Novo Nordisk Fonden|NNF15OC0016584, Rosetrees|M179, Rosetrees|M630, The Francis Crick Institute|10169, The Francis Crick Institute|10202, The Francis Crick Institute|10002, The Francis Crick Institute|10233, Wellcome Trust|107963/Z/15/Z, Wellcome Trust|211179/Z/18/Z)status: Publishe
Mesothelioma and Radical Surgery 2 (MARS 2): protocol for a multicentre randomised trial comparing (extended) pleurectomy decortication versus no (extended) pleurectomy decortication for patients with malignant pleural mesothelioma.
No full textINTRODUCTION: Mesothelioma remains a lethal cancer. To date, systemic therapy with pemetrexed and a platinum drug remains the only licensed standard of care. As the median survival for patients with mesothelioma is 12.1 months, surgery is an important consideration to improve survival and/or quality of life. Currently, only two surgical trials have been performed which found that neither extensive (extra-pleural pneumonectomy) or limited (partial pleurectomy) surgery improved survival (although there was some evidence of improved quality of life). Therefore, clinicians are now looking to evaluate pleurectomy decortication, the only radical treatment option left. METHODS AND ANALYSIS: The MARS 2 study is a UK multicentre open parallel group randomised controlled trial comparing the effectiveness and cost-effectiveness of surgery-(extended) pleurectomy decortication-versus no surgery for the treatment of pleural mesothelioma. The study will test the hypothesis that surgery and chemotherapy is superior to chemotherapy alone with respect to overall survival. Secondary outcomes include health-related quality of life, progression-free survival, measures of safety (adverse events) and resource use to 2 years. The QuinteT Recruitment Intervention is integrated into the trial to optimise recruitment. ETHICS AND DISSEMINATION: Research ethics approval was granted by London - Camberwell St. Giles Research Ethics Committee (reference 13/LO/1481) on 7 November 2013. We will submit the results for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBERS: ISRCTN-ISRCTN44351742 and ClinicalTrials.gov-NCT02040272
Publisher Correction: Pulmonary venous circulating tumor cell dissemination before tumor resection and disease relapse
No full textPublisher Correction: Spatial heterogeneity of the T cell receptor repertoire reflects the mutational landscape in lung cancer
No full textCorrection to: Nature Medicine https://doi.org/10.1038/s41591-019-0592-2, published online 7 October 2019
Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.
No full textWith the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches
Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors
No full textCD25 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-CD25
antibodies were observed to deplete Treg cells in
the periphery, upregulation of the inhibitory Fc
gamma receptor (FcgR) IIb at the tumor site prevented
intra-tumoral Treg cell depletion, which may
underlie the lack of anti-tumor activity previously
observed in pre-clinical models. Use of an antiCD25
antibody with enhanced binding to activating
FcgRs led to effective depletion of tumor-infiltrating
Treg cells, increased effector to Treg cell ratios,
and improved control of established tumors. Combination
with anti-programmed cell death protein-1
antibodies promoted complete tumor rejection,
demonstrating the relevance of CD25 as a therapeutic
target and promising substrate for future combination
approaches in immune-oncology
