Subclonal immune evasion in non-small cell lung cancer.

Dijkstra, Krijn K; Vendramin, Roberto; Karagianni, Despoina; Witsen, Maartje; Gálvez-Cancino, Felipe; Hill, Mark S; Foster, Kane A; Barbè, Vittorio; Angelova, Mihaela; Hynds, Robert E; Pearce, David R; Martínez-Ruiz, Carlos; Black, James RM; Huebner, Ariana; Pich, Oriol; Rowan, Andrew; Augustine, Marcellus; Puttick, Clare; Moore, David A; Liu, Lydia L; Saghafinia, Sadegh; van de Haar, Joris; Veeriah, Selvaraju; Naceur-Lombardelli, Cristina; Toncheva, Antonia; Bola, Supreet Kaur; Hiley, Crispin T; Jamal-Hanjani, Mariam; McGranahan, Nicholas; Litchfield, Kevin; Reading, James L; Chain, Benny; consortium, TRACERx; Quezada, Sergio A; Voest, Emile E; Swanton, Charles

Subclonal immune evasion in non-small cell lung cancer.

journal contribution

posted on 2025-10-16, 09:25 authored by Krijn K Dijkstra, Roberto Vendramin, Despoina Karagianni, Maartje Witsen, Felipe Gálvez-Cancino, Mark S Hill, Kane A Foster, Vittorio Barbè, Mihaela Angelova, Robert E Hynds, David R Pearce, Carlos Martínez-Ruiz, James RM Black, Ariana Huebner, Oriol Pich, Andrew Rowan, Marcellus Augustine, Clare Puttick, David A Moore, Lydia 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, TRACERx consortium, Sergio A Quezada, Emile E Voest, Charles Swanton

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.