Role of different epigenetic drugs in reshaping murine melanoma tumor microenvironment

To highlight the role of epigenetics in immune responses, we exploited a model of melanoma using B16F10 injected subcutaneously in syngeneic C57black6j mice and studied the effect of inhibitors of (i) BET bromodomain (OTX-015) (ii) DNA methyltransferase (DNMT) (guadecitabine) on in vivo tumour growth. OTX-015 showed significant in vivo effects in reducing tumour growth in our setting. Guadecitabine induced MHC class I expression on tumour cells, but the latter also increased immune checkpoint expression on cancer cells. Each epigenetic agent altered the tumour microenvironment (TME), mostly by reducing immune suppression, particularly of Tregs or MDSC, or both. OTX-015 and guadecitabine had strong effects, but in opposite ways. OTX-015 downmodulated antitumour responses, whereas guadecitabine remodeled the TME to be more immune-responsive. Epigenetic therapy may enhance immunotherapy, but specific schedules for treatments need to be studied for each drug. Among the drugs tested, guadecitabine seems to be the most promising drug for successful combination immunotherapy. RNAseq gene expression analysis on B16F10 cell line tumor samples derived from mice treated or not with VORINOSTAT (3 treated 3 untreated) Contributor: EPigenetic Immune-oncology Consortium Airc (EPICA)