Cell
Volume 171, Issue 6, 30 November 2017, Pages 1259-1271.e11
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Article
Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution

https://doi.org/10.1016/j.cell.2017.10.001Get rights and content
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Highlights

  • LOHHLA enables estimation of allele-specific HLA loss from sequencing data

  • LOH of the HLA locus occurs in 40% of early stage non-small-cell lung cancers

  • HLA LOH is associated with a high subclonal neoantigen burden and immune activity

  • HLA LOH is an immune escape mechanism subject to strong selection pressures

Summary

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens.

Keywords

immune-escape
copy number
neoantigen
heterogeneity
cancer evolution
immune-editing
loss of heterozygosity
bioinformatics
chromosomal instability
lung cancer

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These authors contributed equally

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