Inhibiting Histone and DNA Methylation Improves Cancer Vaccination in an Experimental Model of Melanoma

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.

The Role and Mechanism of the Histone Methyltransferase G9a in Tumors: Update

“…Consistent with a transient delay in tumor growth and enhanced IFN-I response in immunocompetent mice, improving the efficacy of T-cell receptor redirected T and dendritic cell vaccines, thereby increasing the overall survival of tumor-bearing mice. 86 Furthermore, there are 3D-QSAR pharmacophore-based studies presenting novel and safer lead compounds targeting G9a, which have reduced the toxicity and increased the value of G9a inhibitors in therapeutic applications. 87 …”

Enhancing Immunogenicity in Metastatic Melanoma: Adjuvant Therapies to Promote the Anti-Tumor Immune Response

“…In addition to histone deacetylase inhibitors, which have been shown to improve melanoma cell responsiveness to therapy, other epigenetic modulations have also been shown to promote immunogenicity within the TIME. For example, a dual inhibitor of histone and DNA methyltransferases was shown to induce apoptosis in B16-F10 melanoma and subsequently resulted in increased activation of CD4+ and CD8+ T-cells within the TIME and tumor growth delay [ 67 ]. The chromatin modifier lysine-specific demethylase 1 (LSD1) is an example of an epigenetic target that has also been shown to inhibit anti-tumor immunity [ 68 ].…”