Methylation of RAD51B, XRCC3 and Other Homologous Recombination Genes Is Associated With Expression of Immune Checkpoints and an Inflammatory Signature in Squamous Cell Carcinoma of the Head and Neck, Lung and Cervix

Oncotarget. 2016 Nov 15;7(46):75379-75393. doi: 10.18632/oncotarget.12211.

Abstract

Immune checkpoints are emerging treatment targets, but mechanisms underlying checkpoint expression are poorly understood. Since alterations in DNA repair genes have been connected to the efficacy of checkpoint inhibitors, we investigated associations between methylation of DNA repair genes and CTLA4 and CD274 (PD-L1) expression.A list of DNA repair genes (179 genes) was selected from the literature, methylation status and expression of inflammation-associated genes (The Cancer Genome Atlas data) was correlated in head and neck squamous cell carcinoma (HNSCC), cervical and lung squamous cell carcinoma.A significant positive correlation of the methylation status of 15, 3 and 2 genes with checkpoint expression was identified, respectively. RAD51B methylation was identified in all cancer subtypes. In HNSCC and cervical cancer, there was significant enrichment for homologous recombination genes. Methylation of the candidate genes was also associated with expression of other checkpoints, ligands, MHC- and T-cell associated genes as well as an interferon-inflammatory immune gene signature, predictive for the efficacy of PD-1 inhibition in HNSCC.Homologous recombination deficiency might therefore be mediated by DNA repair gene hypermethylation and linked to an immune-evasive phenotype in SCC. The methylation status of these genes could represent a new predictive biomarker for immune checkpoint inhibition.

Keywords: DNA repair; HRD; immune checkpoints; immune therapy; inflamed gene expression signature.

MeSH terms

  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism
  • Biomarkers
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / immunology
  • DNA Methylation*
  • DNA Repair
  • DNA-Binding Proteins / genetics*
  • Epigenesis, Genetic*
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / immunology
  • Homologous Recombination
  • Humans
  • Immunomodulation / genetics
  • Inflammation
  • Lung Neoplasms / genetics
  • Lung Neoplasms / immunology
  • Male
  • Mutation
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / immunology

Substances

  • B7-H1 Antigen
  • Biomarkers
  • CD274 protein, human
  • DNA-Binding Proteins
  • RAD51B protein, human
  • X-ray repair cross complementing protein 3