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

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; Mariam Jamal-Hanjani; Seema Shafi; Justyna Czyzewska-Khan; Diana Johnson; Joanne Laycock; Leticia Bosshard-Carter; Pat Gorman; Robert E. Hynds; Gareth Wilson; Stuart Horswell; Richard Mitter; Mickael Escudero; Aengus Stewart; Andrew Rowan; Hang Xu; Samra Turajlic; Christopher Abbosh; Jacki Goldman; Richard Kevin Stone; Tamara Denner; Nik Matthews; Greg Elgar; Sophia Ward; Marta Costa; Sharmin Begum; Ben Phillimore; Tim Chambers; Emma Nye; Sofia Graca; Maise Al Bakir; Kroopa Joshi; Andrew Furness; Assma Ben Aissa; Yien Ning Sophia Wong; Andy Georgiou; Sergio Quezada; John A. Hartley; Helen L. Lowe; 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 Thakrar; Martin Forster; Tanya Ahmad; Siow Ming Lee; Dionysis Papadatos-Pastos; Dawn Carnell; Ruheena Mendes; Jeremy George; Neal Navani; Asia Ahmed; Magali Taylor; Junaid Choudhary; Yvonne Summers; Raffaele Califano; Paul Taylor; Rajesh Shah; Piotr Krysiak; Kendadai Rammohan; Eustace Fontaine; Richard Booton; Matthew Evison; Phil Crosbie; Stuart Moss; Faiza Idries; Leena Joseph; Paul 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 Fennell; Jacqui A. 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; Marianne Nicolson; Keith Kerr; Shirley Palmer; Hardy Remmen; Joy Miller; Keith Buchan; Mahendran Chetty; Lesley Gomersall; Jason Lester; Alison Edwards; Fiona 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 Ottensmeier; Serena Chee; Benjamin 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 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 Gosney; Pieter Postmus; Sarah Feeney; Julius Asante-Siaw; Hugo J.W.L. Aerts; Stefan Dentro; Christophe Dessimoz

doi:10.1016/j.cell.2017.10.001

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

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, Mariam Jamal-Hanjani, Seema Shafi, Justyna Czyzewska-Khan, Diana Johnson, Joanne Laycock, Leticia Bosshard-Carter, Pat Gorman, Robert E. Hynds, Gareth WilsonStuart Horswell, Richard Mitter, Mickael Escudero, Aengus Stewart, Andrew Rowan, Hang Xu, Samra Turajlic, Christopher Abbosh, Jacki Goldman, Richard Kevin Stone, Tamara Denner, Nik Matthews, Greg Elgar, Sophia Ward, Marta Costa, Sharmin Begum, Ben Phillimore, Tim Chambers, Emma Nye, Sofia Graca, Maise Al Bakir, Kroopa Joshi, Andrew Furness, Assma Ben Aissa, Yien Ning Sophia Wong, Andy Georgiou, Sergio Quezada, John A. Hartley, Helen L. Lowe, 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 Thakrar, Martin Forster, Tanya Ahmad, Siow Ming Lee, Dionysis Papadatos-Pastos, Dawn Carnell, Ruheena Mendes, Jeremy George, Neal Navani, Asia Ahmed, Magali Taylor, Junaid Choudhary, Yvonne Summers, Raffaele Califano, Paul Taylor, Rajesh Shah, Piotr Krysiak, Kendadai Rammohan, Eustace Fontaine, Richard Booton, Matthew Evison, Phil Crosbie, Stuart Moss, Faiza Idries, Leena Joseph, Paul 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 Fennell, Jacqui A. 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, Marianne Nicolson, Keith Kerr, Shirley Palmer, Hardy Remmen, Joy Miller, Keith Buchan, Mahendran Chetty, Lesley Gomersall, Jason Lester, Alison Edwards, Fiona 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 Ottensmeier, Serena Chee, Benjamin 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 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 Gosney, Pieter Postmus, Sarah Feeney, Julius Asante-Siaw, Hugo J.W.L. Aerts, Stefan Dentro, Christophe Dessimoz

Research output: Contribution to journal › Article › peer-review

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Abstract

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.

Original language	English
Pages (from-to)	1259-1271.e11
Journal	Cell
Volume	171
Issue number	6
Early online date	26 Oct 2017
DOIs	https://doi.org/10.1016/j.cell.2017.10.001
Publication status	Published - 30 Nov 2017

Keywords

immune-escape
copy number
neoantigen
heterogeneity
cancer evolution
immune-editing
loss of heterozygosity
bioinformatics
chromosomal instability
lung cancer

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2017.10.001Licence: CC BY

Allele-Specific HLA Loss_MCGRANAHAN_Firstonline26October2017_GOLD VoR (CC BY)
ª 2017 The Francis Crick Institute. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Final published version, 10.4 MBLicence: CC BY

Cite this

McGranahan, N., Rosenthal, R., Hiley, C. T., Rowan, A. J., Watkins, T. B. K., Wilson, G. A., Birkbak, N. J., Veeriah, S., Van Loo, P., Herrero, J., Swanton, C., Jamal-Hanjani, M., Shafi, S., Czyzewska-Khan, J., Johnson, D., Laycock, J., Bosshard-Carter, L., Gorman, P., Hynds, R. E., ... Dessimoz, C. (2017). Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution. Cell, 171(6), 1259-1271.e11. https://doi.org/10.1016/j.cell.2017.10.001

@article{584bc91856b546c4baebab91fac3e4a5,

title = "Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution",

abstract = "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.",

keywords = "immune-escape, copy number, neoantigen, heterogeneity, cancer evolution, immune-editing, loss of heterozygosity, bioinformatics, chromosomal instability, lung cancer",

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

year = "2017",

month = nov,

day = "30",

doi = "10.1016/j.cell.2017.10.001",

language = "English",

volume = "171",

pages = "1259--1271.e11",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "6",

}

McGranahan, N, Rosenthal, R, Hiley, CT, Rowan, AJ, Watkins, TBK, Wilson, GA, Birkbak, NJ, Veeriah, S, Van Loo, P, Herrero, J, Swanton, C, Jamal-Hanjani, M, Shafi, S, Czyzewska-Khan, J, Johnson, D, Laycock, J, Bosshard-Carter, L, Gorman, P, Hynds, RE, Wilson, G, Horswell, S, Mitter, R, Escudero, M, Stewart, A, Rowan, A, Xu, H, Turajlic, S, Abbosh, C, Goldman, J, Stone, RK, Denner, T, Matthews, N, Elgar, G, Ward, S, Costa, M, Begum, S, Phillimore, B, Chambers, T, Nye, E, Graca, S, Al Bakir, M, Joshi, K, Furness, A, Ben Aissa, A, Wong, YNS, Georgiou, A, Quezada, S, Hartley, JA, Lowe, HL, Lawrence, D, Hayward, M, Panagiotopoulos, N, Kolvekar, S, Falzon, M, Borg, E, Marafioti, T, Simeon, C, Hector, G, Smith, A, Aranda, M, Novelli, M, Oukrif, D, Janes, SM, Thakrar, R, Forster, M, Ahmad, T, Lee, SM, Papadatos-Pastos, D, Carnell, D, Mendes, R, George, J, Navani, N, Ahmed, A, Taylor, M, Choudhary, J, Summers, Y, Califano, R, Taylor, P, Shah, R, Krysiak, P, Rammohan, K, Fontaine, E, Booton, R, Evison, M, Crosbie, P, Moss, S, Idries, F, Joseph, L, Bishop, P, Chaturved, A, Quinn, AM, Doran, H, Leek, A, Harrison, P, Moore, K, Waddington, R, Novasio, J, Blackhall, F, Rogan, J, Smith, E, Dive, C, Tugwood, J, Brady, G, Rothwell, DG, Chemi, F, Pierce, J, Gulati, S, Naidu, B, Langman, G, Trotter, S, Bellamy, M, Bancroft, H, Kerr, A, Kadiri, S, Webb, J, Middleton, G, Djearaman, M, Fennell, D, Shaw, JA, Le Quesne, J, Moore, D, Nakas, A, Rathinam, S, Monteiro, W, Marshall, H, Nelson, L, Bennett, J, Riley, J, Primrose, L, Martinson, L, Anand, G, Khan, S, Amadi, A, Nicolson, M, Kerr, K, Palmer, S, Remmen, H, Miller, J, Buchan, K, Chetty, M, Gomersall, L, Lester, J, Edwards, A, Morgan, F, Adams, H, Davies, H, Kornaszewska, M, Attanoos, R, Lock, S, Verjee, A, MacKenzie, M, Wilcox, M, Bell, H, Hackshaw, A, Ngai, Y, Smith, S, Gower, N, Ottensmeier, C, Chee, S, Johnson, B, Alzetani, A, Shaw, E, Lim, E, De Sousa, P, Barbosa, MT, Bowman, A, Jordan, S, Rice, A, Raubenheimer, H, Proli, C, Cufari, ME, Ronquillo, JC, Kwayie, A, Bhayani, H, Hamilton, M, Bakar, Y, Mensah, N, Ambrose, L, Devaraj, A, Buderi, S, Finch, J, Azcarate, L, Chavan, H, Green, S, Mashinga, H, Nicholson, AG, Lau, K, Sheaff, M, Schmid, P, Conibear, J, Ezhil, V, Ismail, B, Irvin-sellers, M, Prakash, V, Russell, P, Light, T, Horey, T, Danson, S, Bury, J, Edwards, J, Hill, J, Matthews, S, Kitsanta, Y, Suvarna, K, Fisher, P, Keerio, AD, Shackcloth, M, Gosney, J, Postmus, P, Feeney, S, Asante-Siaw, J, Aerts, HJWL, Dentro, S & Dessimoz, C 2017, 'Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution', Cell, vol. 171, no. 6, pp. 1259-1271.e11. https://doi.org/10.1016/j.cell.2017.10.001

TY - JOUR

T1 - Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

AU - McGranahan, Nicholas

AU - Rosenthal, Rachel

AU - Hiley, Crispin T.

AU - Rowan, Andrew J.

AU - Watkins, Thomas B.K.

AU - Wilson, Gareth A.

AU - Birkbak, Nicolai J.

AU - Veeriah, Selvaraju

AU - Van Loo, Peter

AU - Herrero, Javier

AU - Swanton, Charles

AU - Jamal-Hanjani, Mariam

AU - Shafi, Seema

AU - Czyzewska-Khan, Justyna

AU - Johnson, Diana

AU - Laycock, Joanne

AU - Bosshard-Carter, Leticia

AU - Gorman, Pat

AU - Hynds, Robert E.

AU - Wilson, Gareth

AU - Horswell, Stuart

AU - Mitter, Richard

AU - Escudero, Mickael

AU - Stewart, Aengus

AU - Rowan, Andrew

AU - Xu, Hang

AU - Turajlic, Samra

AU - Abbosh, Christopher

AU - Goldman, Jacki

AU - Stone, Richard Kevin

AU - Denner, Tamara

AU - Matthews, Nik

AU - Elgar, Greg

AU - Ward, Sophia

AU - Costa, Marta

AU - Begum, Sharmin

AU - Phillimore, Ben

AU - Chambers, Tim

AU - Nye, Emma

AU - Graca, Sofia

AU - Al Bakir, Maise

AU - Joshi, Kroopa

AU - Furness, Andrew

AU - Ben Aissa, Assma

AU - Wong, Yien Ning Sophia

AU - Georgiou, Andy

AU - Quezada, Sergio

AU - Hartley, John A.

AU - Lowe, Helen L.

AU - Lawrence, David

AU - Hayward, Martin

AU - Panagiotopoulos, Nikolaos

AU - Kolvekar, Shyam

AU - Falzon, Mary

AU - Borg, Elaine

AU - Marafioti, Teresa

AU - Simeon, Celia

AU - Hector, Gemma

AU - Smith, Amy

AU - Aranda, Marie

AU - Novelli, Marco

AU - Oukrif, Dahmane

AU - Janes, Sam M.

AU - Thakrar, Ricky

AU - Forster, Martin

AU - Ahmad, Tanya

AU - Lee, Siow Ming

AU - Papadatos-Pastos, Dionysis

AU - Carnell, Dawn

AU - Mendes, Ruheena

AU - George, Jeremy

AU - Navani, Neal

AU - Ahmed, Asia

AU - Taylor, Magali

AU - Choudhary, Junaid

AU - Summers, Yvonne

AU - Califano, Raffaele

AU - Taylor, Paul

AU - Shah, Rajesh

AU - Krysiak, Piotr

AU - Rammohan, Kendadai

AU - Fontaine, Eustace

AU - Booton, Richard

AU - Evison, Matthew

AU - Crosbie, Phil

AU - Moss, Stuart

AU - Idries, Faiza

AU - Joseph, Leena

AU - Bishop, Paul

AU - Chaturved, Anshuman

AU - Quinn, Anne Marie

AU - Doran, Helen

AU - Leek, Angela

AU - Harrison, Phil

AU - Moore, Katrina

AU - Waddington, Rachael

AU - Novasio, Juliette

AU - Blackhall, Fiona

AU - Rogan, Jane

AU - Smith, Elaine

AU - Dive, Caroline

AU - Tugwood, Jonathan

AU - Brady, Ged

AU - Rothwell, Dominic G.

AU - Chemi, Francesca

AU - Pierce, Jackie

AU - Gulati, Sakshi

AU - Naidu, Babu

AU - Langman, Gerald

AU - Trotter, Simon

AU - Bellamy, Mary

AU - Bancroft, Hollie

AU - Kerr, Amy

AU - Kadiri, Salma

AU - Webb, Joanne

AU - Middleton, Gary

AU - Djearaman, Madava

AU - Fennell, Dean

AU - Shaw, Jacqui A.

AU - Le Quesne, John

AU - Moore, David

AU - Nakas, Apostolos

AU - Rathinam, Sridhar

AU - Monteiro, William

AU - Marshall, Hilary

AU - Nelson, Louise

AU - Bennett, Jonathan

AU - Riley, Joan

AU - Primrose, Lindsay

AU - Martinson, Luke

AU - Anand, Girija

AU - Khan, Sajid

AU - Amadi, Anita

AU - Nicolson, Marianne

AU - Kerr, Keith

AU - Palmer, Shirley

AU - Remmen, Hardy

AU - Miller, Joy

AU - Buchan, Keith

AU - Chetty, Mahendran

AU - Gomersall, Lesley

AU - Lester, Jason

AU - Edwards, Alison

AU - Morgan, Fiona

AU - Adams, Haydn

AU - Davies, Helen

AU - Kornaszewska, Malgorzata

AU - Attanoos, Richard

AU - Lock, Sara

AU - Verjee, Azmina

AU - MacKenzie, Mairead

AU - Wilcox, Maggie

AU - Bell, Harriet

AU - Hackshaw, Allan

AU - Ngai, Yenting

AU - Smith, Sean

AU - Gower, Nicole

AU - Ottensmeier, Christian

AU - Chee, Serena

AU - Johnson, Benjamin

AU - Alzetani, Aiman

AU - Shaw, Emily

AU - Lim, Eric

AU - De Sousa, Paulo

AU - Barbosa, Monica Tavares

AU - Bowman, Alex

AU - Jordan, Simon

AU - Rice, Alexandra

AU - Raubenheimer, Hilgardt

AU - Proli, Chiara

AU - Cufari, Maria Elena

AU - Ronquillo, John Carlo

AU - Kwayie, Angela

AU - Bhayani, Harshil

AU - Hamilton, Morag

AU - Bakar, Yusura

AU - Mensah, Natalie

AU - Ambrose, Lyn

AU - Devaraj, Anand

AU - Buderi, Silviu

AU - Finch, Jonathan

AU - Azcarate, Leire

AU - Chavan, Hema

AU - Green, Sophie

AU - Mashinga, Hillaria

AU - Nicholson, Andrew G.

AU - Lau, Kelvin

AU - Sheaff, Michael

AU - Schmid, Peter

AU - Conibear, John

AU - Ezhil, Veni

AU - Ismail, Babikir

AU - Irvin-sellers, Melanie

AU - Prakash, Vineet

AU - Russell, Peter

AU - Light, Teresa

AU - Horey, Tracey

AU - Danson, Sarah

AU - Bury, Jonathan

AU - Edwards, John

AU - Hill, Jennifer

AU - Matthews, Sue

AU - Kitsanta, Yota

AU - Suvarna, Kim

AU - Fisher, Patricia

AU - Keerio, Allah Dino

AU - Shackcloth, Michael

AU - Gosney, John

AU - Postmus, Pieter

AU - Feeney, Sarah

AU - Asante-Siaw, Julius

AU - Aerts, Hugo J.W.L.

AU - Dentro, Stefan

AU - Dessimoz, Christophe

PY - 2017/11/30

Y1 - 2017/11/30

N2 - 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.

AB - 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.

KW - immune-escape

KW - copy number

KW - neoantigen

KW - heterogeneity

KW - cancer evolution

KW - immune-editing

KW - loss of heterozygosity

KW - bioinformatics

KW - chromosomal instability

KW - lung cancer

UR - http://www.scopus.com/inward/record.url?scp=85032583704&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2017.10.001

DO - 10.1016/j.cell.2017.10.001

M3 - Article

SN - 0092-8674

VL - 171

SP - 1259-1271.e11

JO - Cell

JF - Cell

IS - 6

ER -

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

Abstract

Keywords

UN SDGs

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