Abstract：
: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. VIDEO ABSTRACT.
journal_name
Celljournal_title
Cellauthors
McGranahan N,Rosenthal R,Hiley CT,Rowan AJ,Watkins TBK,Wilson GA,Birkbak NJ,Veeriah S,Van Loo P,Herrero J,Swanton C,TRACERx Consortium.doi
10.1016/j.cell.2017.10.001subject
Has Abstractpub_date
2017-11-30 00:00:00pages
1259-1271.e11issue
6eissn
0092-8674issn
1097-4172pii
S0092-8674(17)31185-6journal_volume
171pub_type
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