Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution.
journal contributionposted on 2018-04-10, 11:43 authored by N. McGranahan, R. Rosenthal, C. T. Hiley, A. J. Rowan, T. B. K. Watkins, G. A. Wilson, N. J. Birkbak, S. Veeriah, P. Van Loo, J. Herrero, C. Swanton, TRACERx Consortium, Dean Fennell
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.
CitationCell, 2017, 171 (6), pp. 1259-1271.e11
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Cancer Research Centre
- VoR (Version of Record)
bioinformaticscancer evolutionchromosomal instabilitycopy numberheterogeneityimmune-editingimmune-escapeloss of heterozygositylung cancerneoantigenAdultAgedAged, 80 and overAntigen PresentationCarcinoma, Non-Small-Cell LungCohort StudiesFemaleHLA AntigensHumansLoss of HeterozygosityLung NeoplasmsMaleMiddle AgedMutationPolymorphism, Single NucleotideTumor Escape