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

Abstract

SummaryImmune 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

Evolutionary Pressure against MHC Class II Binding Cancer Mutations

“…Passenger mutations, defined as mutations occurring only 1-2 times across all tumors in non-cancer genes, had a PHBR-II score distribution very similar to that of random mutations with an enrichment for PHBR-II scores near 0, suggesting that many passengers are likely to be effectively presented. This enrichment of presented passenger mutations is consistent with recent reports that HLA loss of heterozygosity is frequent in some tumor types (Chowell et al, 2017; McGranahan et al, 2017; Ryschich et al, 2004) and is associated with the accumulation of mutations that would have been effectively presented by the lost allele (McGranahan et al, 2017). Consequently, 25% percent of the passenger mutation PHBR-II scores fall below the PHBR-II cutoff of 6 (Figure 3D).…”

Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy

“…Previous work has reported loss of heterozygosity (LOH) of HLA-I genes in cancer (43, 44). We thus analyzed all tumor exomes from cohort 1 and identified 32 patients who were heterozygous at all HLA-I loci but had LOH in at least one HLA-I locus in their tumors (table S1).…”

Cancer evolution and heterogeneity

“…In addition, low‐grade glioma showed an exacerbated diversity in ITH after treatment with the alkylating agent temozolomide 39. In non‐small‐cell lung cancers (NSCLC) and bladder cancer, the apolipoprotein B mRNA editing enzyme, catalytic polypeptide‐like (APOBEC) family of proteins was associated with fostering many subclones (signature 2) 19, 20, 40…”

“…Losing the ability to present neoantigens, as a result of human leukocyte antigen (HLA) loss, may facilitate immune evasion. McGranahan et al40 reported that HLA loss of heterozygosity (LOH) occurs in 40% of NSCLC. LOH is an immune escape mechanism that is subject to strong microenvironment later in tumor evolution.…”