AUTHOR=De Beck Lien , Awad Robin Maximilian , Basso Veronica , Casares Noelia , De Ridder Kirsten , De Vlaeminck Yannick , Gnata Alessandra , Goyvaerts Cleo , Lecocq Quentin , San José-Enériz Edurne , Verhulst Stefaan , Maes Ken , Vanderkerken Karin , Agirre Xabier , Prosper Felipe , Lasarte Juan José , Mondino Anna , Breckpot Karine TITLE=Inhibiting Histone and DNA Methylation Improves Cancer Vaccination in an Experimental Model of Melanoma JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.799636 DOI=10.3389/fimmu.2022.799636 ISSN=1664-3224 ABSTRACT=

Immunotherapy has improved the treatment of malignant skin cancer of the melanoma type, yet overall clinical response rates remain low. Combination therapies could be key to meet this cogent medical need. Because epigenetic hallmarks represent promising combination therapy targets, we studied the immunogenic potential of a dual inhibitor of histone methyltransferase G9a and DNA methyltransferases (DNMTs) in the preclinical B16-OVA melanoma model. Making use of tumor transcriptomic and functional analyses, methylation-targeted epigenetic reprogramming was shown to induce tumor cell cycle arrest and apoptosis in vitro coinciding with transient tumor growth delay and an IFN-I response in immune-competent mice. In consideration of a potential impact on immune cells, the drug was shown not to interfere with dendritic cell maturation or T-cell activation in vitro. Notably, the drug promoted dendritic cell and, to a lesser extent, T-cell infiltration in vivo, yet failed to sensitize tumor cells to programmed cell death-1 inhibition. Instead, it increased therapeutic efficacy of TCR-redirected T cell and dendritic cell vaccination, jointly increasing overall survival of B16-OVA tumor-bearing mice. The reported data confirm the prospect of methylation-targeted epigenetic reprogramming in melanoma and sustain dual G9a and DNMT inhibition as a strategy to tip the cancer-immune set-point towards responsiveness to active and adoptive vaccination against melanoma.