Clonal driver neoantigen loss under EGFR TKI and immune selection pressures

• 成果类型: Article
• 署名作者: Al Bakir, Maise; Reading, James L.; Gamble, Samuel; Rosenthal, Rachel; Uddin, Imran; Rowan, Andrew; Przewrocka, Joanna; Rogers, Amber; Wong, Yien Ning Sophia; Bentzen, Amalie K.; Veeriah, Selvaraju; Ward, Sophia; Garnett, Aaron T.; Kalavakur, Paula; Martinez-Ruiz, Carlos; Puttick, Clare; Huebner, Ariana; Cook, Daniel E.; Moore, David A.; Abbosh, Chris; Hiley, Crispin T.; Naceur-Lombardelli, Cristina; Watkins, Thomas B. K.; Petkovic, Marina; Schwarz, Roland F.; Galvez-Cancino, Felipe; Litchfield, Kevin; Meldgaard, Peter; Sorensen, Boe Sandahl; Madsen, Line Bille; Jaeger, Dirk; Forster, Martin D.; Arkenau, Tobias; Domingo-Vila, Clara; Tree, Timothy I. M.; Kadivar, Mohammad; Hadrup, Sine Reker; Chain, Benny; Quezada, Sergio A.; McGranahan, Nicholas; Swanton, Charles
• 署名单位: Francis Crick Institute; Cancer Research UK; University of London; University College London; University of London; University College London; University of London; University College London; Francis Crick Institute; University of London; University College London; University College London Hospitals NHS Foundation Trust; University of London; University College London; Helmholtz Association; Max Delbruck Center for Molecular Medicine; Humboldt University of Berlin; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; University of Cologne; University of Cologne; University of Oxford; Aarhus University; Aarhus University; Aarhus University; Ruprecht Karls University Heidelberg; University of London; University College London; University of London; University College London
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3031
• DOI: 10.1038/s41586-025-08586-y
• 发表日期: 2025-03-27
• 关键词: cell lung-cancer; acquired-resistance; EVOLUTION; tumor; mechanisms; immunotherapy

摘要

Neoantigen vaccines are under investigation for various cancers, including epidermal growth factor receptor (EGFR)-driven lung cancers1,2. We tracked the phylogenetic history of an EGFR mutant lung cancer treated with erlotinib, osimertinib, radiotherapy and a personalized neopeptide vaccine (NPV) targeting ten somatic mutations, including EGFR exon 19 deletion (ex19del). The ex19del mutation was clonal, but is likely to have appeared after a whole-genome doubling (WGD) event. Following osimertinib and NPV treatment, loss of the ex19del mutation was identified in a progressing small-cell-transformed liver metastasis. Circulating tumour DNA analyses tracking 467 somatic variants revealed the presence of this EGFR wild-type clone before vaccination and its expansion during osimertinib/NPV therapy. Despite systemic T cell reactivity to the vaccine-targeted ex19del neoantigen, the NPV failed to halt disease progression. The liver metastasis lost vaccine-targeted neoantigens through chromosomal instability and exhibited a hostile microenvironment, characterized by limited immune infiltration, low CXCL9 and elevated M2 macrophage levels. Neoantigens arising post-WGD were more likely to be absent in the progressing liver metastasis than those occurring pre-WGD, suggesting that prioritizing pre-WGD neoantigens may improve vaccine design. Data from the TRACERx 421 cohort3 provide evidence that pre-WGD mutations better represent clonal variants, and owing to their presence at multiple copy numbers, are less likely to be lost in metastatic transition. These data highlight the power of phylogenetic disease tracking and functional T cell profiling to understand mechanisms of immune escape during combination therapies.