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Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

2017; Cell Press; Volume: 171; Issue: 6 Linguagem: Inglês

10.1016/j.cell.2017.10.001

1097-4172

Nicholas McGranahan, Rachel Rosenthal, Crispin T. Hiley, Andrew J. Rowan, Thomas B.K. Watkins, Gareth A. Wilson, Nicolai J. Birkbak, Selvaraju Veeriah, Peter Van Loo, Javier Herrero, Charles Swanton, Charles Swanton, Mariam Jamal‐Hanjani, Selvaraju Veeriah, Seema Shafi, Justyna Czyzewska-Khan, Diana Johnson, Joanne Laycock, Leticia Bosshard‐Carter, Rachel Rosenthal, Pat Gorman, Robert E. Hynds, Gareth A. Wilson, Nicolai J. Birkbak, Thomas B.K. Watkins, Nicholas McGranahan, Stuart Horswell, Richard Mitter, Mickael Escudero, Aengus Stewart, Peter Van Loo, Andrew Rowan, Hang Xu, Samra Turajlic, Crispin T. Hiley, Christopher Abbosh, Jacki Goldman, Richard Stone, Tamara Denner, Nik Matthews, Greg Elgar, Martin Hayward, Marta Costa, Sharmin Begum, Ben Phillimore, Tim Chambers, Emma Nye, Sofia Graca, Maise Al Bakir, Kroopa Joshi, Andrew J.S. Furness, Assma Ben Aïssa, Yien Ning Sophia Wong, Andy Georgiou, Sergio A. Quezada, John A. Hartley, Helen L. Lowe, Javier Herrero, David Lawrence, Martin Hayward, Nikolaos Panagiotopoulos, Shyam Kolvekar, Mary Falzon, Elaine Borg, Teresa Marafioti, Celia Simeon, Gemma Hector, Amy Smith, Marie Aranda, Marco Novelli, Dahmane Oukrif, Sam M. Janes, Ricky M. Thakrar, Martin Förster, Tanya Ahmad, SM Lee, Dionysis Papadatos-Pastos, Dawn Carnell, R. Mendes, Jeremy George, Neal Navani, Asia Ahmed, Magali N. Taylor, Junaid Choudhary, Yvonne Summers, Raffaele Califano, P. W. J. Taylor, Rajesh Shah, Piotr Krysiak, Kendadai Rammohan, Eustace Fontaine, Richard Booton, Matthew Evison, Philip Crosbie, Stuart Moss, Faiza Idries, Leena Dennis Joseph, Paul N. Bishop, Anshuman Chaturved, Anne Marie Quinn, Helen Doran, Angela Leek, Phil Harrison, Katrina Moore, Rachael Waddington, Juliette Novasio, Fiona Blackhall, Jane Rogan, Elaine Smith, Caroline Dive, Jonathan Tugwood, Ged Brady, Dominic G. Rothwell, Francesca Chemi, Jackie Pierce, Sakshi Gulati, Babu Naidu, Gerald Langman, Simon Trotter, Mary Bellamy, Hollie Bancroft, Amy Kerr, Salma Kadiri, Joanne Webb, Gary Middleton, Madava Djearaman, Dean A. Fennell, Jacqui Shaw, John Le Quesne, David Moore, Apostolos Nakas, Sridhar Rathinam, William Monteiro, Hilary Marshall, Louise Nelson, Jonathan Bennett, Joan Riley, Lindsay Primrose, Luke Martinson, Girija Anand, Sajid Khan, Anita Amadi, M. Nicolson, Keith M. Kerr, Shirley Palmer, Hardy Remmen, J. Richard Miller, Keith Buchan, Mahendran Chetty, Lesley Gomersall, J.F. Lester, Alison Edwards, Fiona J. E. Morgan, Haydn Adams, Helen Davies, Malgorzata Kornaszewska, Richard Attanoos, Sara Lock, Azmina Verjee, Mairead MacKenzie, Maggie Wilcox, Harriet Bell, Allan Hackshaw, Yenting Ngai, Sean Smith, Nicole Gower, Christian H. Ottensmeier, Serena Chee, Benjamin M. Johnson, Aiman Alzetani, Emily Shaw, Eric Lim, Paulo De Sousa, Monica Tavares Barbosa, Alex Bowman, Simon Jordan, Alexandra Rice, Hilgardt Raubenheimer, Chiara Proli, Maria Elena Cufari, John Carlo Ronquillo, Angela Kwayie, Harshil Bhayani, Morag Hamilton, Yusura Bakar, Natalie Mensah, Lyn Ambrose, Anand Devaraj, Silviu Buderi, Jonathan Finch, Leire Azcarate, Hema Chavan, Sophie M. Green, Hillaria Mashinga, Andrew G. Nicholson, Kelvin Lau, Michael Sheaff, Peter Schmid, John Conibear, Veni Ezhil, Babikir Ismail, Melanie Irvin-Sellers, Vineet Prakash, Peter Russell, Teresa Light, Tracey Horey, Sarah Danson, Jonathan Bury, John Edwards, Jennifer Hill, Sue Matthews, Yota Kitsanta, Kim Suvarna, Patricia Fisher, Allah Dino Keerio, Michael Shackcloth, John R. Gosney, Pieter E. Postmus, Sarah Feeney, Julius Asante-Siaw, Hugo J.W.L. Aerts, Stefan C. Dentro, Christophe Dessimoz,

Cancer Immunotherapy and Biomarkers

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 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.Video AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJjNWY2YzMxODYzZmM5ZTVhMDgyYWUyYTkwODU5NDBhZCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc5MDEzNzE2fQ.OnMgbMlGwv3H5SJXIJmxz_yYlMeeOOR5dzJh9wIi9fxq-4HHj-iVTs8sgzerK5TvDe6i8DM_hsD1WgkrXgw0LsGFfKu44XgKYcgfnGz8FYyz6ZSDcdyfMRGpyVxyopCvcf2V6IlU92HY-88ajBjuG9WA_yaDG1Zm3625ja4_p1_CyU784lBB5tlitic5VoQHTrLhBZqm1hElGyLKqj-cwGOZzRGviS3QIOhKHjjwk6n9hu6fSDbLGNTdVlRSjP0w6mKXoNmLRD1meiP3xqJAB8kuC9Fo-3XAJbRuCsAitjFeQZkcsRdlepUhcgl-GKPOJmGyfQ8Yg1vAtnFLtk3VtQ(mp4, (13.69 MB) Download video