Abstract
Neoantigen presentation arises as a result of tumor-specific mutations and is a critical component of immune surveillance that can be abrogated by somatic LOH of the human leukocyte antigen class I (HLA-I) locus. To understand the role of HLA-I LOH in oncogenesis and treatment, we utilized a pan-cancer genomic dataset of 83,644 patient samples, a small subset of which had treatment outcomes with immune checkpoint inhibitors (ICI). HLA-I LOH was common (17%) and unexpectedly had a nonlinear relationship with tumor mutational burden (TMB). HLA-I LOH was frequent at intermediate TMB, yet prevalence decreased above 30 mutations/megabase, suggesting highly mutated tumors require alternate immune evasion mechanisms. In ICI-treated patients with nonsquamous non-small cell lung cancer, HLA-I LOH was a significant negative predictor of overall survival. Survival prediction improved when combined with TMB, suggesting TMB with HLA-I LOH may better identify patients likely to benefit from ICIs. SIGNIFICANCE: This work shows the pan-cancer landscape of HLA-I LOH, revealing an unexpected "Goldilocks" relationship between HLA-I LOH and TMB, and demonstrates HLA-I LOH as a significant negative predictor of outcomes after ICI treatment. These data informed a combined predictor of outcomes after ICI and have implications for tumor vaccine development.This article is highlighted in the In This Issue feature, p. 211.
Highlights
Immune checkpoint inhibitors (ICI) have revolutionized current treatments for patients with advanced cancer by reinvigorating one’s own T cell–mediated immune response [1, 2]
To assess the landscape of allele-specific human leukocyte antigen class I (HLA-I) LOH, we developed a pipeline for tumor-only next-generation sequencing (NGS) of tissue biopsies that can detect LOH as well as germline homozygosity at the HLA-I locus (HLA-A, HLA-B, and HLA-C)
We describe the landscape of HLA-I LOH across 59 different tumor types totaling 83,664 samples
Summary
Immune checkpoint inhibitors (ICI) have revolutionized current treatments for patients with advanced cancer by reinvigorating one’s own T cell–mediated immune response [1, 2]. We show that somatic HLA-I LOH is a poor prognostic for OS in ICI-treated patients with nonsquamous NSCLC and ablates the survival benefit attributed to high TMB, suggesting that HLA-I LOH is a potential escape mechanism for immune responses against tumor neoantigens. This conclusion is further supported by demonstrating that the HLA-I allele predicted to present a driver neoantigen is the allele that is preferentially lost by HLA-I LOH. We conclude that considering both TMB and HLA-I LOH biomarkers may better identify patients likely to benefit from ICI treatment
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