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. 2021 Feb;11(2):282-292.
doi: 10.1158/2159-8290.CD-20-0672. Epub 2020 Oct 30.

Somatic HLA Class I Loss Is a Widespread Mechanism of Immune Evasion Which Refines the Use of Tumor Mutational Burden as a Biomarker of Checkpoint Inhibitor Response

Meagan Montesion  1 , Karthikeyan Murugesan  1 , Dexter X Jin  1 , Radwa Sharaf  1 , Nora Sanchez  1 , Ameet Guria  1 , Max Minker  1 , Gerald Li  1 , Virginia Fisher  1 , Ethan S Sokol  1 , Dean C Pavlick  1 , Jay A Moore  1 , Alan Braly  1 , Gaurav Singal  1 , David Fabrizio  1 , Leah A Comment  1 , Naiyer A Rizvi  2 , Brian M Alexander  1 , Garrett M Frampton  1 , Priti S Hegde  1 , Lee A Albacker  3
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Somatic HLA Class I Loss Is a Widespread Mechanism of Immune Evasion Which Refines the Use of Tumor Mutational Burden as a Biomarker of Checkpoint Inhibitor Response

Meagan Montesion et al. Cancer Discov. 2021 Feb.

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.

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