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

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,…

• PC
  Prostate Cancer Foundation
• BC
  Breast Cancer Research Foundation
• FC
  Francis Crick Institute
• CR
  Cancer Research UK

  Awards: FC001202, C11496/A17786, FC001169
• NI
  National Institute for Health and Care Research
• UC
  University College London

  Award: UCL/12/0279
• RT
  Rosetrees Trust
• MR
  Medical Research Council

  Awards: MR/P024351/1, FC001202, FC001169
• UB
  UCLH Biomedical Research Centre
• NC
  National Cancer Institute