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.
Highlights
Cancer is a heterogeneous disease that is caused by alterations of the genome
Identification of a DNA repair gene methylation immune signature in squamous cell cancer types In head and neck squamous cell carcinoma (HNSCC), hypermethylation of 19 genes was identified to correlate with CD274 expression according to the defined cutoff. 16 genes were identified to correlate with CTLA4. 15 genes were present in both subsets and included in the HNSCC DNA repair gene candidate list (XRCC1, MLH3, PMS1, RAD51 Paralog B (RAD51B), XRCC3, RAD54B, BRCA1, SHFM1, GEN1, FANCE, FAAP20, SPRTN, SETMAR, HUS1, and PER1)
In lung squamous cell carcinoma, 38 genes were identified for CTLA4, 20 genes for CD274 expression. 2 genes were present in both subsets and included in the lung squamous candidate list (RAD51B, CHEK1)
Summary
Cancer is a heterogeneous disease that is caused by alterations of the genome. DNA damage, evolutionary selection and dysfunctional DNA repair. This leads to a change in the structure of several intracellular proteins. Expression of www.impactjournals.com/oncotarget immune checkpoint molecules and/or ligands that lead to T-cell inactivation has been increasingly recognized. Inhibitors of the immune checkpoints CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and CD274 (Programmed death-ligand 1, PD-L1 or B7H1) have been approved for the treatment of several cancer types, further underlining the importance of this pathway [2]. Several checkpoint inhibitors are in clinical trials for advanced squamous cell solid tumors, including cervical carcinoma (e.g. NCT01693783 [5], NCT01693562 [6] and others)
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