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

TLDR

Immune evasion is a hallmark of cancer, and loss of HLA‑mediated neoantigen presentation can facilitate this process, but the polymorphic nature of the HLA locus has hindered accurate copy‑number analysis. The authors introduce LOHHLA, a computational method to determine allele‑specific HLA copy number from sequencing data. LOHHLA infers HLA loss of heterozygosity by analyzing sequencing read depth and allele frequencies to compute allele‑specific copy numbers. Using LOHHLA, the authors found that HLA loss of heterozygosity occurs in 40 % of non‑small‑cell lung cancers, is linked to high subclonal neoantigen burden, APOBEC mutagenesis, increased cytolytic activity, and PD‑L1 expression, and is frequently focal, subclonal, enriched in metastatic sites, and arises as parallel events—demonstrating it as a microenvironment‑driven immune‑escape mechanism with implications for neoantigen‑based therapies.

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 AbstracteyJraWQiOiI4ZjUxYWNhY2IzYjhiNjNlNzFlYmIzYWFmYTU5NmZmYyIsImFsZyI6IlJTMjU2In0.eyJzdWIiOiJjNWY2YzMxODYzZmM5ZTVhMDgyYWUyYTkwODU5NDBhZCIsImtpZCI6IjhmNTFhY2FjYjNiOGI2M2U3MWViYjNhYWZhNTk2ZmZjIiwiZXhwIjoxNjc5MDEzNzE2fQ.OnMgbMlGwv3H5SJXIJmxz_yYlMeeOOR5dzJh9wIi9fxq-4HHj-iVTs8sgzerK5TvDe6i8DM_hsD1WgkrXgw0LsGFfKu44XgKYcgfnGz8FYyz6ZSDcdyfMRGpyVxyopCvcf2V6IlU92HY-88ajBjuG9WA_yaDG1Zm3625ja4_p1_CyU784lBB5tlitic5VoQHTrLhBZqm1hElGyLKqj-cwGOZzRGviS3QIOhKHjjwk6n9hu6fSDbLGNTdVlRSjP0w6mKXoNmLRD1meiP3xqJAB8kuC9Fo-3XAJbRuCsAitjFeQZkcsRdlepUhcgl-GKPOJmGyfQ8Yg1vAtnFLtk3VtQ(mp4, (13.69 MB) Download video