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  • 1
    Publication Date: 2016-03-05
    Description: 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 intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8(+)tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non-small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy-induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉McGranahan, Nicholas -- Furness, Andrew J S -- Rosenthal, Rachel -- Ramskov, Sofie -- Lyngaa, Rikke -- Saini, Sunil Kumar -- Jamal-Hanjani, Mariam -- Wilson, Gareth A -- Birkbak, Nicolai J -- Hiley, Crispin T -- Watkins, Thomas B K -- Shafi, Seema -- Murugaesu, Nirupa -- Mitter, Richard -- Akarca, Ayse U -- Linares, Joseph -- Marafioti, Teresa -- Henry, Jake Y -- Van Allen, Eliezer M -- Miao, Diana -- Schilling, Bastian -- Schadendorf, Dirk -- Garraway, Levi A -- Makarov, Vladimir -- Rizvi, Naiyer A -- Snyder, Alexandra -- Hellmann, Matthew D -- Merghoub, Taha -- Wolchok, Jedd D -- Shukla, Sachet A -- Wu, Catherine J -- Peggs, Karl S -- Chan, Timothy A -- Hadrup, Sine R -- Quezada, Sergio A -- Swanton, Charles -- 12100/Cancer Research UK/United Kingdom -- 1R01CA155010-02/CA/NCI NIH HHS/ -- 1R01CA182461-01/CA/NCI NIH HHS/ -- 1R01CA184922-01/CA/NCI NIH HHS/ -- Cancer Research UK/United Kingdom -- New York, N.Y. -- Science. 2016 Mar 25;351(6280):1463-9. doi: 10.1126/science.aaf1490. Epub 2016 Mar 3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉The Francis Crick Institute, London WC2A 3LY, UK. Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London (UCL), London WC1E 6BT, UK. Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. ; Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. Cancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UK. ; Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. ; Section for Immunology and Vaccinology, National Veterinary Institute, Technical University of Denmark, 1970 Frederiksberg C, Denmark. ; The Francis Crick Institute, London WC2A 3LY, UK. Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. ; The Francis Crick Institute, London WC2A 3LY, UK. ; Cancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UK. Department of Cellular Pathology, UCL, London WC1E 6BT, UK. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany. German Cancer Consortium (DKTK), 69121 Heidelberg, Germany. ; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Hematology/Oncology Division, 177 Fort Washington Avenue, Columbia University, New York, NY 10032, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Medical College, New York, NY 10065, USA. Ludwig Collaborative Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Department of Medicine, Harvard Medical School, Boston, MA 02115, USA. Department of Internal Medicine, Brigham and Woman's Hospital, Boston, MA 02115, USA. ; Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. Cancer Immunology Unit, UCL Cancer Institute, UCL, London WC1E 6BT, UK. s.quezada@ucl.ac.uk charles.swanton@crick.ac.uk. ; The Francis Crick Institute, London WC2A 3LY, UK. Cancer Research UK Lung Cancer Centre of Excellence, UCL Cancer Institute, London WC1E 6BT, UK. s.quezada@ucl.ac.uk charles.swanton@crick.ac.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26940869" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/drug therapy/genetics/*immunology ; Aged ; Aged, 80 and over ; Antigens, Neoplasm/genetics/*immunology ; Antineoplastic Agents/therapeutic use ; CD4-Positive T-Lymphocytes/*immunology ; CTLA-4 Antigen/immunology ; Carcinoma, Non-Small-Cell Lung/genetics/immunology ; Cell Cycle Checkpoints/immunology ; Female ; Humans ; *Immunologic Surveillance ; Lung Neoplasms/drug therapy/genetics/*immunology ; Lymphocytes, Tumor-Infiltrating/immunology ; Male ; Melanoma/immunology ; Middle Aged ; Mutation ; Programmed Cell Death 1 Receptor/immunology ; Skin Neoplasms/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2014-10-11
    Description: Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636050/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636050/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉de Bruin, Elza C -- McGranahan, Nicholas -- Mitter, Richard -- Salm, Max -- Wedge, David C -- Yates, Lucy -- Jamal-Hanjani, Mariam -- Shafi, Seema -- Murugaesu, Nirupa -- Rowan, Andrew J -- Gronroos, Eva -- Muhammad, Madiha A -- Horswell, Stuart -- Gerlinger, Marco -- Varela, Ignacio -- Jones, David -- Marshall, John -- Voet, Thierry -- Van Loo, Peter -- Rassl, Doris M -- Rintoul, Robert C -- Janes, Sam M -- Lee, Siow-Ming -- Forster, Martin -- Ahmad, Tanya -- Lawrence, David -- Falzon, Mary -- Capitanio, Arrigo -- Harkins, Timothy T -- Lee, Clarence C -- Tom, Warren -- Teefe, Enock -- Chen, Shann-Ching -- Begum, Sharmin -- Rabinowitz, Adam -- Phillimore, Benjamin -- Spencer-Dene, Bradley -- Stamp, Gordon -- Szallasi, Zoltan -- Matthews, Nik -- Stewart, Aengus -- Campbell, Peter -- Swanton, Charles -- 088340/Wellcome Trust/United Kingdom -- 091730/Wellcome Trust/United Kingdom -- 105104/Wellcome Trust/United Kingdom -- A11590/Cancer Research UK/United Kingdom -- A17786/Cancer Research UK/United Kingdom -- A19310/Cancer Research UK/United Kingdom -- A4688/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Oct 10;346(6206):251-6. doi: 10.1126/science.1253462.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. ; Cancer Research UK London Research Institute, London WC2A 3LY, UK. Centre for Mathematics and Physics in the Life Science and Experimental Biology (CoMPLEX), University College London, London WC1E 6BT, UK. ; Cancer Research UK London Research Institute, London WC2A 3LY, UK. ; Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. ; Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. University of Cambridge, Cambridge CB2 1TN, UK. ; Instituto de Biomedicina y Biotecnologia de Cantabria (CSIC-UC-Sodercan), Departamento de Biologia Molecular, Universidad de Cantabria, Santander, Spain. ; Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium. ; Papworth Hospital NHS Foundation Trust, Cambridge CB23 3RE, UK. ; Lungs for Living Research Centre, University College London, London WC1E 6BT, UK. ; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. University College London Hospitals, London NW1 2BU, UK. ; University College London Hospitals, London NW1 2BU, UK. ; Thermo Fisher Scientific, Carlsbad, CA 92008, USA. ; Technical University of Denmark, 2800 Kongens Lyngby, Denmark. Children's Hospital Informatics Program, Harvard Medical School, Boston, MA 02115, USA. ; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. Cancer Research UK London Research Institute, London WC2A 3LY, UK. charles.swanton@cancer.org.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25301630" target="_blank"〉PubMed〈/a〉
    Keywords: Carcinogens/toxicity ; Carcinoma, Non-Small-Cell Lung/chemically induced/*diagnosis/*genetics ; Cytidine Deaminase/genetics ; Evolution, Molecular ; Gene Dosage ; *Genetic Heterogeneity ; *Genomic Instability ; Humans ; Lung Neoplasms/chemically induced/*diagnosis/*genetics ; Mutation ; Neoplasm Recurrence, Local/genetics ; Prognosis ; Smoking/adverse effects ; Translocation, Genetic ; Tumor Cells, Cultured
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 3
    Abstract: 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 intratumor heterogeneity (ITH) on antitumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas. CD8(+)tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non-small cell lung cancer and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC and melanoma was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy-induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens.
    Type of Publication: Journal article published
    PubMed ID: 26940869
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  • 4
    ISSN: 0300-9629
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 0031-9422
    Keywords: Angiosperms ; biogenesis. ; gallic acid metabolism ; taxonomy
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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