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

By Nicholas McGranahan, R. Rosenthal, C. Hiley, Andrew Rowan, T. Watkins, G. Wilson, Nicolai J. Birkbak, S. Veeriah, P. van Loo, Javier Herrero and 202 more. Cell, 2017

1,156 citations recorded by the source corpus.

Summary 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 Abstract

Subfields: Immunology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/05596ed5781efe7d4de1ea19db563714ef01d871

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Citations in the corpus

Detection of mosaic and population-level structural variants with Sniffles2 (2024, neutral): “Sniffles2 remains open source (MIT license) and is available at https://github.com/fritzsedlazeck/Sniffles.”
Cancer Immune Evasion Through Loss of MHC Class I Antigen Presentation (2021, background): “Loss of both copies of MHC I heavy chain genes or of ß2M will eliminate essentially all MHC I expression, and such loss does occur in cancers (96, 141, 158, 159).”
Integrative molecular and clinical modeling of clinical outcomes to PD-1 blockade in metastatic melanoma patients (2019, neutral): “LOH in HLA-A, B, or C 28 was not associated with response or resistance to therapy (Fisher’s exact p=0.52, 0.57, 0.84, respectively).”
Neoantigens: promising targets for cancer therapy (2023, methodology): “4% of cases had a loss of heterozygosity (LOH) in the HLA, which increased the possibility that a fusion neoantigen would be present.(78,83) These results demonstrate the significance of gene fusions as a source of tumor-specific neoantigens.”
Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal (2018, result): “…increased allelic imbalance at the human leukocyte antigen (HLA) locus in selected versus non-selected clones (HLA allelic imbalanceobserved inn=12 ‘‘selected’’ vs. n=2 ‘‘not selected’’ clones; Table S3), consistent with the recent findings in non-small-cell lung cancer (McGranahan et al., 2017).”
HLA variation and disease (2018, background): “…has also found that certain tumours display recurrent somatic mutations in HLA genes 88 , including mutations that promote a loss of HLA allele heterozygosity 89 ; consequently, such tumours are more likely to undergo immune eva sion as there is lessefficient presentation of tumour neoantigens.”