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. In a study published in CELL we present the computational tool LOHHLA (Loss Of Heterozygosity in Human Leukocyte Antigen), which can be used to determine HLA allele-specific copy number from sequencing data.
Using LOHHLA, we find that HLA LOH occurs in 40% of early stage 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.
Reference: Allele-Specific HLA Loss and Immune Escape in Lung Cancer Evolution; CELL, October (2017).