Decitabine increases neoantigen and cancer testis antigen expression to enhance T cell-mediated toxicity against glioblastoma.
Ma R., Rei M., Woodhouse I., Ferris K., Kirschner S., Chandran A., Gileadi U., Chen J-L., Pereira Pinho M., Ariosa-Morejon Y., Kriaucionis S., Ternette N., Koohy H., Ansorge O., Ogg G., Plaha P., Cerundolo V.
BACKGROUND: Glioblastoma (GBM) is the most common and malignant primary brain tumour in adults. Despite maximal treatment, median survival remains dismal at 14-24 months. Immunotherapies, such as checkpoint inhibition, have revolutionised management of some cancers but have little benefit for GBM patients. This is, in part, due to the low mutational and neoantigen burden in this immunogenically 'cold' tumour. METHODS: U87MG and patient derived cell lines were treated with 5-aza-2'-deoxycytidine (DAC) and underwent whole exome and transcriptome sequencing. Cell lines were then subjected to cellular assays with neoantigen and cancer testis antigen (CTA) specific T cells. RESULTS: We demonstrate that DAC increases neoantigen and CTA mRNA expression through DNA hypomethylation. This results in increased neoantigen presentation by MHC class I in tumour cells, leading to increased neoantigen- and CTA-specific T cell activation and killing of DAC-treated cancer cells. In addition, we show that patients have endogenous cancer-specific T cells in both tumour and blood, which show increased tumour-specific activation in the presence of DAC-treated cells. CONCLUSIONS: Our work shows that DAC increases GBM immunogenicity and consequent susceptibility to T cell responses in-vitro. Our results support a potential use of DAC as a sensitizing agent to immunotherapy.