Neoantigen-directed immune escape in lung cancer evolution,Nature

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Neoantigen-directed immune escape in lung cancer evolution
Nature ( IF 50.5 ) Pub Date : 2019-03-01 , DOI: 10.1038/s41586-019-1032-7
Rachel Rosenthal _{1,

2,

3} , Elizabeth Larose Cadieux ₄ , Roberto Salgado _{5,

6} , Maise Al Bakir ₃ , David A Moore ₇ , Crispin T Hiley _{1,

3} , Tom Lund _{8,

9} , Miljana Tanić ₁₀ , James L Reading _{8,

9} , Kroopa Joshi _{8,

9} , Jake Y Henry _{8,

9} , Ehsan Ghorani _{8,

9} , Gareth A Wilson _{1,

3} , Nicolai J Birkbak _{1,

3} , Mariam Jamal-Hanjani ₁ , Selvaraju Veeriah ₁ , Zoltan Szallasi _{11,

12} , Sherene Loi ₆ , Matthew D Hellmann _{13,

14} , Andrew Feber ₁₅ , Benny Chain _{16,

17} , Javier Herrero ₂ , Sergio A Quezada _{1,

8,

9} , Jonas Demeulemeester _{4,

18} , Peter Van Loo _{4,

18} , Stephan Beck ₁₀ , Nicholas McGranahan _{1,

19} , Charles Swanton _{1,

3} ,

Affiliation

Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, University College London, London, UK.
Bill Lyons Informatics Centre, University College London Cancer Institute, University College London, London, UK.
Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
Cancer Genomics Laboratory, The Francis Crick Institute, London, UK.
Department of Pathology, GZA-ZNA, Antwerp, Belgium.
Division of Research, Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.
Department of Pathology, University College London Cancer Institute, University College London, London, UK.
Cancer Immunology Unit, University College London Cancer Institute, University College London, London, UK.
Research Department of Haematology, University College London Cancer Institute, University College London, London, UK.
Department of Cancer Biology, University College London Cancer Institute, University College London, London, UK.
Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Danish Cancer Society Research Center, Copenhagen, Denmark.
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Weill Cornell Medical College, Cornell University, New York, NY, USA.
Division of Surgery and Interventional Science, University College London, London, UK.
Division of Infection and Immunity, University College London, London, UK.
Department of Computer Sciences, University College London, London, UK.
Department of Human Genetics, University of Leuven, Leuven, Belgium.
Cancer Genome Evolution Research Group, University College London Cancer Institute, University College London, London, UK.

The interplay between an evolving cancer and a dynamic immune microenvironment remains unclear. Here we analyse 258 regions from 88 early-stage, untreated non-small-cell lung cancers using RNA sequencing and histopathology-assessed tumour-infiltrating lymphocyte estimates. Immune infiltration varied both between and within tumours, with different mechanisms of neoantigen presentation dysfunction enriched in distinct immune microenvironments. Sparsely infiltrated tumours exhibited a waning of neoantigen editing during tumour evolution, indicative of historical immune editing, or copy-number loss of previously clonal neoantigens. Immune-infiltrated tumour regions exhibited ongoing immunoediting, with either loss of heterozygosity in human leukocyte antigens or depletion of expressed neoantigens. We identified promoter hypermethylation of genes that contain neoantigenic mutations as an epigenetic mechanism of immunoediting. Our results suggest that the immune microenvironment exerts a strong selection pressure in early-stage, untreated non-small-cell lung cancers that produces multiple routes to immune evasion, which are clinically relevant and forecast poor disease-free survival.RNA sequencing data and tumour pathology observations of non-small-cell lung cancers indicate that the immune cell microenvironment exerts strong evolutionary selection pressures that shape the immune-evasion capacity of tumours.

中文翻译：

肺癌进化过程中新抗原引导的免疫逃逸

不断发展的癌症与动态免疫微环境之间的相互作用仍不清楚。在这里，我们使用 RNA 测序和组织病理学评估的肿瘤浸润淋巴细胞估计分析了 88 个早期、未经治疗的非小细胞肺癌的 258 个区域。肿瘤之间和肿瘤内部的免疫浸润各不相同，不同的免疫微环境中富含新抗原呈递功能障碍的不同机制。稀疏浸润的肿瘤在肿瘤进化过程中表现出新抗原编辑的减弱，表明历史免疫编辑或先前克隆新抗原的拷贝数丢失。免疫浸润的肿瘤区域表现出持续的免疫编辑，人类白细胞抗原杂合性丧失或表达的新抗原耗尽。我们发现含有新抗原突变的基因的启动子高甲基化是免疫编辑的表观遗传机制。我们的结果表明，免疫微环境对早期、未经治疗的非小细胞肺癌施加强大的选择压力，产生多种免疫逃避途径，这与临床相关并预测较差的无病生存率。RNA测序数据和肿瘤非小细胞肺癌的病理观察表明，免疫细胞微环境施加强大的进化选择压力，塑造肿瘤的免疫逃避能力。

更新日期：2019-03-01

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