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Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution.pdf (10.43 MB)

Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution.

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journal contribution
posted 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.

History

Citation

Cell, 2017, 171 (6), pp. 1259-1271.e11

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Cancer Research Centre

Version

  • VoR (Version of Record)

Published in

Cell

Publisher

Elsevier

issn

0092-8674

eissn

1097-4172

Acceptance date

2017-09-28

Copyright date

2017

Available date

2018-04-10

Publisher version

http://www.cell.com/cell/fulltext/S0092-8674(17)31185-6

Language

en