Oral Presentation 16th Asian Conference on Transcription 2019

Methylome and transcriptome programme segregates PD-L1 expressing and non-expressing melanoma (1129)

Aniruddha Chatterjee 1 , Euan J Rodger 1 , Antonio Ahn 1 , Peter A Stockwell 1 , Matthew Parry 1 , Stuart Gallagher 2 , Jessamy Tiffen 2 , Peter Hersey 2 , Michael Eccles 1
  1. University of Otago, Dunedin, OTAGO, New Zealand
  2. Centenary Institute, University of Sydney, Sydney, NSW, Australia

The programmed death-ligand 1 (PD-L1) receptor is an important immune checkpoint and is often upregulated in cancer cells to allow immune evasion. In melanoma, the patients with PD-L1 expression and absence of tumour infiltrating lymphocytes (TILs) (i.e. “constitutive PD-L1 or PD-L1CON”) show worse response rates and prognosis than patients with PD-L1 expression and the presence of TILs (i.e. “inducible PD-L1 or PD-L1IND”). However, how PD-L1 expression is regulated in melanoma cells remains elusive. We hypothesised that epigenetic state regulates constitutive and inducible PD-L1 expression in melanoma.

We have generated whole-genome scale DNA methylomes (using reduced representation bisulfite sequencing) and transcriptomes (RNA-Seq) for patient derived melanoma cell lines (in PD-L1IND and PD-L1CON  groups). We discovered extensive global hypomethylation in the constitutive lines, particularly pronounced in intergenic repeat regions and gene bodies. RNA-Sequencing data indicated that the hypomethylated state of the PD-L1CON cells was correlated with higher upregulation of the differentially expressed genes at a global-scale and the upregulated genes were associated with cancer hallmark properties. Transcriptome signature revealed viral mimicry, oxidative phosphorylation and differentiation as the major altered pathway between PD-L1IND and PD-L1CON melanoma groups and this signature was strongly validated in melanoma patient expression signatures (cancer genome atlas data). We believe these results are the first to show that DNA methylation mediated transcriptome regulation play a role in controlling PD-L1 expression in melanoma and suggest they may have important implications for combined treatments targeting methylation (DNMTi) and PD1/PD-L1 (anti-PD1 antibodies).