Neoantigen directed immune escape in lung cancer evolution
By R. Rosenthal, E. L. Cadieux, R. Salgado, Maise Al Bakir, D. Moore, C. Hiley, T. Lund, M. Tanić, J. Reading, K. Joshi and 18 more. Nature, 2019
783 citations recorded by the source corpus.
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.
Subfields: Immunology, Oncology
View Paper: https://www.semanticscholar.org/paper/a2c2ad36f28b1c8ef735508a8da5f4e6b4b9f6bd
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Citations in the corpus
- Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation (2021, background): “Cancer neoantigen genes can also be subjected to DNA hypermethylation (189).”
- Acquired Resistance to Immune Checkpoint Inhibitors (2020, background): “Consequently, loss of the somatic mutations encoding putative tumor-specific neoantigens either through clonal selection, epigenetic repression, or copy number loss may lead to subsequent immune evasion and clinical progression (Rosenthal et al., 2019).”
- Inflammation and Cancer: Triggers, Mechanisms and Consequences (2019, background): “It has become clear now that the immune system can play significant pro- and anti-tumorigenic roles at all stages of the tumorigenesis (Koebel et al., 2007; McGranahan and Swanton, 2017; Rosenthal et al., 2019; Schreiber et al., 2011; Teng et al., 2008; Vesely et al., 2011; Zilionis et al., 2019).”
- Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “Based on the frequency and location of immune cells tumors can be classified as immune cold (immune desert), peritumoral, stromal-restricted, and inflamed (Gruosso et al., 2019; Keren et al., 2018; Rosenthal et al., 2019).”
- Neoantigens: promising targets for cancer therapy (2023, background): “The mutant genes encoding non-expressed neoantigens have enriched hypermethylation at their promoter regions compared with the wild-type parental genes in other purity/ ploidy matched samples.(486) In addition, tumors can alter the presentation of neoantigens via modulating protein turnover.”