Geospatial immune variability illuminates differential evolution of lung adenocarcinoma
Khalid AbdulJabbar, Shan E Ahmed Raza, Rachel Rosenthal, Mariam Jamal-Hanjani, Selvaraju Veeriah, Ayse Akarca, Tom Lund, David A Moore, Roberto Salgado, Maise Al Bakir, Luis Zapata, Crispin T Hiley, Leah Officer, Marco Sereno, Claire Rachel Smith, Sherene Loi, Allan Hackshaw, Teresa Marafioti, Sergio A Quezada, Nicholas McGranahan, John Le Quesne, TRACERx Consortium, Charles Swanton, Yinyin Yuan, Charles Swanton, Mariam Jamal-Hanjani, John Le Quesne, Allan Hackshaw, Sergio A Quezada, Nicholas McGranahan, Rachel Rosenthal, Crispin T Hiley, Selvaraju Veeriah, David A Moore, Maise Al Bakir, Teresa Marafioti, Roberto Salgado, Yenting Ngai, Abigail Sharp, Cristina Rodrigues, Oliver Pressey, Sean Smith, Nicole Gower, Harjot Dhanda, Joan Riley, Lindsay Primrose, Luke Martinson, Nicolas Carey, Jacqui A Shaw, Dean Fennell, Gareth A Wilson, Nicolai J Birkbak, Thomas B K Watkins, Mickael Escudero, Aengus Stewart, Andrew Rowan, Jacki Goldman, Peter Van Loo, Richard Kevin Stone, Tamara Denner, Emma Nye, Sophia Ward, Emilia L Lim, Stefan Boeing, Maria Greco, Kevin Litchfield, Jerome Nicod, Clare Puttick, Katey Enfield, Emma Colliver, Brittany Campbell, Christopher Abbosh, Yin Wu, Marcin Skrzypski, Robert E Hynds, Andrew Georgiou, Mariana Werner Sunderland, James L Reading, Karl S Peggs, John A Hartley, Pat Gorman, Helen L Lowe, Leah Ensell, Victoria Spanswick, Angeliki Karamani, Dhruva Biswas, Maryam Razaq, Stephan Beck, Ariana Huebner, Michelle Dietzen, Cristina Naceur-Lombardelli, Mita Afroza Akther, Haoran Zhai, Nnennaya Kannu, Elizabeth Manzano, Supreet Kaur Bola, Ehsan Ghorani, Marc Robert de Massy, Elena Hoxha, Emine Hatipoglu, Stephanie Ogwuru, Benny Chain, Gillian Price, Sylvie Dubois-Marshall, Keith Kerr, Shirley Palmer, Heather Cheyne, Joy Miller, Keith Buchan, Mahendran Chetty, Mohammed Khalil, Veni Ezhil, Vineet Prakash, Girija Anand, Sajid Khan, Kelvin Lau, Michael Sheaff, Peter Schmid, Louise Lim, John Conibear, Roland Schwarz, Jonathan Tugwood, Jackie Pierce, Caroline Dive, Ged Brady, Dominic G Rothwell, Francesca Chemi, Elaine Kilgour, Fiona Blackhall, Lynsey Priest, Matthew G Krebs, Philip Crosbie, Apostolos Nakas, Sridhar Rathinam, Louise Nelson, Kim Ryanna, Mohamad Tuffail, Amrita Bajaj, Jan Brozik, Fiona Morgan, Malgorzata Kornaszewska, Richard Attanoos, Haydn Adams, Helen Davies, Mathew Carter, C R Lindsay, Fabio Gomes, Zoltan Szallasi, Istvan Csabai, Miklos Diossy, Hugo Aerts, Alan Kirk, Mo Asif, John Butler, Rocco Bilanca, Nikos Kostoulas, Mairead MacKenzie, Maggie Wilcox, Sara Busacca, Alan Dawson, Mark R Lovett, Michael Shackcloth, Sarah Feeney, Julius Asante-Siaw, John Gosney, Angela Leek, Nicola Totten, Jack Davies Hodgkinson, Rachael Waddington, Jane Rogan, Katrina Moore, William Monteiro, Hilary Marshall, Kevin G Blyth, Craig Dick, Andrew Kidd, Eric Lim, Paulo De Sousa, Simon Jordan, Alexandra Rice, Hilgardt Raubenheimer, Harshil Bhayani, Morag Hamilton, Lyn Ambrose, Anand Devaraj, Hema Chavan, Sofina Begum, Aleksander Mani, Daniel Kaniu, Mpho Malima, Sarah Booth, Andrew G Nicholson, Nadia Fernandes, Jessica E Wallen, Pratibha Shah, Sarah Danson, Jonathan Bury, John Edwards, Jennifer Hill, Sue Matthews, Yota Kitsanta, Jagan Rao, Sara Tenconi, Laura Socci, Kim Suvarna, Faith Kibutu, Patricia Fisher, Robin Young, Joann Barker, Fiona Taylor, Kirsty Lloyd, Teresa Light, Tracey Horey, Dionysis Papadatos-Pastos, Peter Russell, Sara Lock, Kayleigh Gilbert, David Lawrence, Martin Hayward, Nikolaos Panagiotopoulos, Robert George, Davide Patrini, Mary Falzon, Elaine Borg, Reena Khiroya, Asia Ahmed, Magali Taylor, Junaid Choudhary, Penny Shaw, Sam M Janes, Martin Forster, Tanya Ahmad, Siow Ming Lee, Javier Herrero, Dawn Carnell, Ruheena Mendes, Jeremy George, Neal Navani, Marco Scarci, Elisa Bertoja, Robert C M Stephens, Emilie Martinoni Hoogenboom, James W Holding, Steve Bandula, Babu Naidu, Gerald Langman, Andrew Robinson, Hollie Bancroft, Amy Kerr, Salma Kadiri, Charlotte Ferris, Gary Middleton, Madava Djearaman, Akshay Patel, Christian Ottensmeier, Serena Chee, Benjamin Johnson, Aiman Alzetani, Emily Shaw, Jason Lester, Yvonne Summers, Raffaele Califano, Paul Taylor, Rajesh Shah, Piotr Krysiak, Kendadai Rammohan, Eustace Fontaine, Richard Booton, Matthew Evison, Stuart Moss, Juliette Novasio, Leena Joseph, Paul Bishop, Anshuman Chaturvedi, Helen Doran, Felice Granato, Vijay Joshi, Elaine Smith, Angeles Montero, Khalid AbdulJabbar, Shan E Ahmed Raza, Rachel Rosenthal, Mariam Jamal-Hanjani, Selvaraju Veeriah, Ayse Akarca, Tom Lund, David A Moore, Roberto Salgado, Maise Al Bakir, Luis Zapata, Crispin T Hiley, Leah Officer, Marco Sereno, Claire Rachel Smith, Sherene Loi, Allan Hackshaw, Teresa Marafioti, Sergio A Quezada, Nicholas McGranahan, John Le Quesne, TRACERx Consortium, Charles Swanton, Yinyin Yuan, Charles Swanton, Mariam Jamal-Hanjani, John Le Quesne, Allan Hackshaw, Sergio A Quezada, Nicholas McGranahan, Rachel Rosenthal, Crispin T Hiley, Selvaraju Veeriah, David A Moore, Maise Al Bakir, Teresa Marafioti, Roberto Salgado, Yenting Ngai, Abigail Sharp, Cristina Rodrigues, Oliver Pressey, Sean Smith, Nicole Gower, Harjot Dhanda, Joan Riley, Lindsay Primrose, Luke Martinson, Nicolas Carey, Jacqui A Shaw, Dean Fennell, Gareth A Wilson, Nicolai J Birkbak, Thomas B K Watkins, Mickael Escudero, Aengus Stewart, Andrew Rowan, Jacki Goldman, Peter Van Loo, Richard Kevin Stone, Tamara Denner, Emma Nye, Sophia Ward, Emilia L Lim, Stefan Boeing, Maria Greco, Kevin Litchfield, Jerome Nicod, Clare Puttick, Katey Enfield, Emma Colliver, Brittany Campbell, Christopher Abbosh, Yin Wu, Marcin Skrzypski, Robert E Hynds, Andrew Georgiou, Mariana Werner Sunderland, James L Reading, Karl S Peggs, John A Hartley, Pat Gorman, Helen L Lowe, Leah Ensell, Victoria Spanswick, Angeliki Karamani, Dhruva Biswas, Maryam Razaq, Stephan Beck, Ariana Huebner, Michelle Dietzen, Cristina Naceur-Lombardelli, Mita Afroza Akther, Haoran Zhai, Nnennaya Kannu, Elizabeth Manzano, Supreet Kaur Bola, Ehsan Ghorani, Marc Robert de Massy, Elena Hoxha, Emine Hatipoglu, Stephanie Ogwuru, Benny Chain, Gillian Price, Sylvie Dubois-Marshall, Keith Kerr, Shirley Palmer, Heather Cheyne, Joy Miller, Keith Buchan, Mahendran Chetty, Mohammed Khalil, Veni Ezhil, Vineet Prakash, Girija Anand, Sajid Khan, Kelvin Lau, Michael Sheaff, Peter Schmid, Louise Lim, John Conibear, Roland Schwarz, Jonathan Tugwood, Jackie Pierce, Caroline Dive, Ged Brady, Dominic G Rothwell, Francesca Chemi, Elaine Kilgour, Fiona Blackhall, Lynsey Priest, Matthew G Krebs, Philip Crosbie, Apostolos Nakas, Sridhar Rathinam, Louise Nelson, Kim Ryanna, Mohamad Tuffail, Amrita Bajaj, Jan Brozik, Fiona Morgan, Malgorzata Kornaszewska, Richard Attanoos, Haydn Adams, Helen Davies, Mathew Carter, C R Lindsay, Fabio Gomes, Zoltan Szallasi, Istvan Csabai, Miklos Diossy, Hugo Aerts, Alan Kirk, Mo Asif, John Butler, Rocco Bilanca, Nikos Kostoulas, Mairead MacKenzie, Maggie Wilcox, Sara Busacca, Alan Dawson, Mark R Lovett, Michael Shackcloth, Sarah Feeney, Julius Asante-Siaw, John Gosney, Angela Leek, Nicola Totten, Jack Davies Hodgkinson, Rachael Waddington, Jane Rogan, Katrina Moore, William Monteiro, Hilary Marshall, Kevin G Blyth, Craig Dick, Andrew Kidd, Eric Lim, Paulo De Sousa, Simon Jordan, Alexandra Rice, Hilgardt Raubenheimer, Harshil Bhayani, Morag Hamilton, Lyn Ambrose, Anand Devaraj, Hema Chavan, Sofina Begum, Aleksander Mani, Daniel Kaniu, Mpho Malima, Sarah Booth, Andrew G Nicholson, Nadia Fernandes, Jessica E Wallen, Pratibha Shah, Sarah Danson, Jonathan Bury, John Edwards, Jennifer Hill, Sue Matthews, Yota Kitsanta, Jagan Rao, Sara Tenconi, Laura Socci, Kim Suvarna, Faith Kibutu, Patricia Fisher, Robin Young, Joann Barker, Fiona Taylor, Kirsty Lloyd, Teresa Light, Tracey Horey, Dionysis Papadatos-Pastos, Peter Russell, Sara Lock, Kayleigh Gilbert, David Lawrence, Martin Hayward, Nikolaos Panagiotopoulos, Robert George, Davide Patrini, Mary Falzon, Elaine Borg, Reena Khiroya, Asia Ahmed, Magali Taylor, Junaid Choudhary, Penny Shaw, Sam M Janes, Martin Forster, Tanya Ahmad, Siow Ming Lee, Javier Herrero, Dawn Carnell, Ruheena Mendes, Jeremy George, Neal Navani, Marco Scarci, Elisa Bertoja, Robert C M Stephens, Emilie Martinoni Hoogenboom, James W Holding, Steve Bandula, Babu Naidu, Gerald Langman, Andrew Robinson, Hollie Bancroft, Amy Kerr, Salma Kadiri, Charlotte Ferris, Gary Middleton, Madava Djearaman, Akshay Patel, Christian Ottensmeier, Serena Chee, Benjamin Johnson, Aiman Alzetani, Emily Shaw, Jason Lester, Yvonne Summers, Raffaele Califano, Paul Taylor, Rajesh Shah, Piotr Krysiak, Kendadai Rammohan, Eustace Fontaine, Richard Booton, Matthew Evison, Stuart Moss, Juliette Novasio, Leena Joseph, Paul Bishop, Anshuman Chaturvedi, Helen Doran, Felice Granato, Vijay Joshi, Elaine Smith, Angeles Montero
Abstract
Remarkable progress in molecular analyses has improved our understanding of the evolution of cancer cells toward immune escape1-5. However, the spatial configurations of immune and stromal cells, which may shed light on the evolution of immune escape across tumor geographical locations, remain unaddressed. We integrated multiregion exome and RNA-sequencing (RNA-seq) data with spatial histology mapped by deep learning in 100 patients with non-small cell lung cancer from the TRACERx cohort6. Cancer subclones derived from immune cold regions were more closely related in mutation space, diversifying more recently than subclones from immune hot regions. In TRACERx and in an independent multisample cohort of 970 patients with lung adenocarcinoma, tumors with more than one immune cold region had a higher risk of relapse, independently of tumor size, stage and number of samples per patient. In lung adenocarcinoma, but not lung squamous cell carcinoma, geometrical irregularity and complexity of the cancer-stromal cell interface significantly increased in tumor regions without disruption of antigen presentation. Decreased lymphocyte accumulation in adjacent stroma was observed in tumors with low clonal neoantigen burden. Collectively, immune geospatial variability elucidates tumor ecological constraints that may shape the emergence of immune-evading subclones and aggressive clinical phenotypes.
Trial registration: ClinicalTrials.gov NCT01888601.
Conflict of interest statement
Competing Interests
Y.Y. has received speakers bureau honoraria from Roche and is a consultant for Merck and Co Inc. C.S. receives grant support from Pfizer, AstraZeneca, BMS, Roche-Ventana, Boehringer-Ingelheim and Ono Pharmaceutical. C.S. has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, BMS, Celgene, AstraZeneca, Illumina, Genentech, Roche-Ventana, GRAIL, Medicxi, and the Sarah Cannon Research Institute. C.S. is a shareholder of Apogen Biotechnologies, Epic Bioscience, GRAIL, and has stock options in and is co-founder of Achilles Therapeutics. M.A.B. is a consultant for Achilles Therapeutics. S.L. receives research funding to her institution from Novartis, Bristol Meyers Squibb, Merck, Roche-Genentech, Puma Biotechnology, Pfizer, Eli Lilly and Seattle Genetics. S.L. has acted as consultant (not compensated) to Seattle Genetics, Pfizer, Novartis, BMS, Merck, AstraZeneca and RocheGenentech. S.L. has acted as consultant (paid to her institution) to Aduro Biotech, Novartis, and G1 Therapeutics. D.A.M. has received speaker’s fees from AstraZeneca. M.J.H. is a member of the Advisory Board for Achilles Therapeutics.
Figures
Source: PubMed