Subclonal immune evasion in non-small cell lung cancer
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Krijn Dijkstra Roberto Vendramin Despoina Karagianni Maartje Witsen Felipe Gálvez-Cancino Mark S Hill Kane A Foster Vittorio Barbè Mihaela Angelova Rob 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
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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.
Journal details
Journal
Cancer Cell
Volume
43
Issue number
10
Pages
1833-1849 .e10
Available online
Publication date
Full text links
Publisher website (DOI)
10.1016/j.ccell.2025.06.012
Figshare
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Europe PubMed Central
40614739
Pubmed
40614739
