| Authors: |
McGranahan, NRosenthal, RHiley, CTRowan, AJWatkins, TBKWilson, GABirkbak, NJVeeriah, SVan Loo, PHerrero, JSwanton, C |
| Item Type: |
Journal Article |
| 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. |
| Issue Date: |
30-Nov-2017 |
| Date of Acceptance: |
28-Sep-2017 |
| URI: |
http://hdl.handle.net/10044/1/74194 |
| DOI: |
https://doi.org/10.1016/j.cell.2017.10.001 |
| ISSN: |
0092-8674 |
| Publisher: |
Elsevier (Cell Press) |
| Start Page: |
1259 |
| End Page: |
1270 |
| Journal / Book Title: |
Cell |
| Volume: |
171 |
| Issue: |
6 |
| Copyright Statement: |
© 2017 The Francis Crick Institute. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: |
Science & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyCell BiologyCOPY NUMBERPD-1 BLOCKADEMUTATIONAL PROCESSESCTLA-4 BLOCKADEDOWN-REGULATIONCELLSNEOANTIGENSSENSITIVITYRESISTANCEDISCOVERYbioinformaticscancer evolutionchromosomal instabilitycopy numberheterogeneityimmune-editingimmune-escapeloss of heterozygositylung cancerneoantigenAdultAgedAged, 80 and overAntigen PresentationCarcinoma, Non-Small-Cell LungCohort StudiesFemaleHLA AntigensHumansLoss of HeterozygosityLung NeoplasmsMaleMiddle AgedMutationPolymorphism, Single NucleotideTumor EscapeTRACERx ConsortiumHumansCarcinoma, Non-Small-Cell LungLung NeoplasmsHLA AntigensCohort StudiesAntigen PresentationTumor EscapeMutationLoss of HeterozygosityPolymorphism, Single NucleotideAdultAgedAged, 80 and overMiddle AgedFemaleMaleScience & TechnologyLife Sciences & BiomedicineBiochemistry & Molecular BiologyCell BiologyCOPY NUMBERPD-1 BLOCKADEMUTATIONAL PROCESSESCTLA-4 BLOCKADEDOWN-REGULATIONCELLSNEOANTIGENSSENSITIVITYRESISTANCEDISCOVERY06 Biological Sciences11 Medical and Health SciencesDevelopmental Biology |
| Publication Status: |
Published |
| Online Publication Date: |
2017-10-26 |
| Appears in Collections: |
National Heart and Lung Institute |