Distinct immune evasion in APOBEC-enriched, HPV-negative HNSCC

Int J Cancer. 2020 Oct 15;147(8):2293-2302. doi: 10.1002/ijc.33123. Epub 2020 Jun 18.


Immune checkpoint inhibition leads to response in some patients with head and neck squamous cell carcinoma (HNSCC). Robust biomarkers are lacking to date. We analyzed viral status, gene expression signatures, mutational load and mutational signatures in whole exome and RNA-sequencing data of the HNSCC TCGA dataset (n = 496) and a validation set (DKTK MASTER cohort, n = 10). Public single-cell gene expression data from 17 HPV-negative HNSCC were separately reanalyzed. APOBEC3-associated TCW motif mutations but not total single nucleotide variant burden were significantly associated with inflammation. This association was restricted to HPV-negative HNSCC samples. An APOBEC-enriched, HPV-negative subgroup was identified, that showed higher T-cell inflammation and immune checkpoint expression, as well as expression of APOBEC3 genes. Mutations in immune-evasion pathways were also enriched in these tumors. Analysis of single-cell sequencing data identified expression of APOBEC3B and 3C genes in malignant cells. We identified an APOBEC-enriched subgroup of HPV-negative HNSCC with a distinct immunogenic phenotype, potentially mediating response to immunotherapy.

Keywords: APOBEC; head and neck cancer; immune checkpoint inhibition; mutational signature; tumor inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • APOBEC Deaminases / genetics*
  • APOBEC Deaminases / immunology*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / immunology
  • Cohort Studies
  • Exome / genetics
  • Exome / immunology
  • Female
  • Gene Expression Regulation, Neoplastic / genetics
  • Gene Expression Regulation, Neoplastic / immunology
  • Head and Neck Neoplasms / immunology*
  • Head and Neck Neoplasms / virology
  • Humans
  • Immune Evasion / genetics*
  • Immune Evasion / immunology*
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / virology
  • Male
  • Middle Aged
  • Mutation / genetics
  • Papillomaviridae / immunology
  • Papillomavirus Infections / genetics
  • Papillomavirus Infections / immunology
  • Papillomavirus Infections / virology
  • Sequence Analysis, RNA / methods
  • Squamous Cell Carcinoma of Head and Neck / genetics*
  • Squamous Cell Carcinoma of Head and Neck / immunology*
  • Squamous Cell Carcinoma of Head and Neck / virology
  • T-Lymphocytes / immunology
  • Transcriptome / genetics
  • Transcriptome / immunology


  • Biomarkers, Tumor
  • APOBEC Deaminases