Subclonal immune evasion in non-small cell lung cancer
Krijn K. Dijkstra, Roberto Vendramin, Despoina Karagianni, Maartje Witsen, Felipe Gálvez‐Cancino, Mark S. Hill, Kane Foster, Vittorio Barbè, Mihaela Angelova, Robert E. Hynds, David R. Pearce, Carlos Martínez‐Ruiz, James R. Black, Ariana Huebner, Oriol Pich, Andrew Rowan, Marcellus Augustine, Clare Puttick, David A. Moore, L. Liu, Sadegh Saghafinia, Joris van de Haar, Selvaraju Veeriah, Cristina Naceur‐Lombardelli, Antonia Toncheva, Supreet Kaur Bola, Crispin T. Hiley, Mariam Jamal‐Hanjani, Nicholas McGranahan, Kevin Litchfield, James L. Reading, Benny Chain, Abigail Bunkum, Adam Atkin, Aiman Alzetani, Akshay J. Patel, Alan Kirk, Alexander James Procter, Alexander M. Frankell, Alexandra Rice, Allan Hackshaw, Amrita Bajaj, Anand Devaraj, Anca Grapa, Andrew G. Nicholson, Andrew Kidd, Andrew Rowan, Angela Dwornik, Angela Leek, Angeliki Karamani, Anne-Marie Hacker, Anshuman Chaturvedi, Antonio Paiva-Correia, Aoife Walker, Apostolos Nakas, Ariana Huebner, Arjun Nair, Asia Ahmed, Aya Osman, Azmina Sodha-Ramdeen, Babu Naidu, Benny Chain, Camilla Pilotti, Carla Castignani, Carlos Martínez-Ruiz, Caroline Dive, Catarina Veiga, Charles Swanton, Charles-Antoine Collins-Fekete, Chiara Proli, Chris Bailey, Cian Murphy, Claire Wilson, Clare E. Weeden, Clare Puttick, Claudia Lee, Colin R. Lindsay, Corentin Richard, Craig Dick, Crispin T. Hiley, Cristina Naceur-Lombardelli, Daniel Kaniu, David A. Moore, David Chuter, David Lawrence, David R. Pearce, Davide Patrini, Dean A. Fennell, Despoina Karagianni, Dionysis Papadatos-Pastos, Ekaterini Boleti, Elaine Borg, Elizabeth Keene, Emilia L. Lim, Emilie Martinoni Hoogenboom, Emma Colliver, Emma Nye, Eric Lim, Erik Sahai, Eustace Fontaine
Abstract
Cancers rarely respond completely to immunotherapy. While tumors consist of multiple genetically distinct clones, whether this affects the potential for immune escape remains unclear due to an inability to isolate and propagate individual subclones from human cancers. Here, we leverage the multi-region TRACERx lung cancer evolution study to generate a patient-derived organoid - T cell co-culture platform that allows the functional analysis of subclonal immune escape at single clone resolution. We establish organoid lines from 11 separate tumor regions from three patients, followed by isolation of 81 individual clonal sublines. Co-culture with tumor infiltrating lymphocytes (TIL) or natural killer (NK) cells reveals cancer-intrinsic and subclonal immune escape in all 3 patients. Immune evading subclones represent genetically distinct lineages with a unique evolutionary history. This indicates that immune evading and non-evading subclones can be isolated from the same tumor, suggesting that subclonal tumor evolution directly affects immune escape.