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

by Selleckchem | Aug 28 2023

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.

Comments:

The text you provided describes a study conducted on the immunogenic potential of a dual inhibitor of histone methyltransferase G9a and DNA methyltransferases (DNMTs) in a preclinical B16-OVA melanoma model. The researchers aimed to evaluate the effectiveness of combination therapies targeting epigenetic hallmarks in treating melanoma, a type of malignant skin cancer.

The study involved analyzing the tumor transcriptome and conducting functional analyses. In vitro experiments showed that the methylation-targeted epigenetic reprogramming induced tumor cell cycle arrest and apoptosis, resulting in a temporary delay in tumor growth. The treatment also triggered an interferon-I (IFN-I) response in immune-competent mice.

To assess the impact on immune cells, the researchers investigated the effects of the drug on dendritic cell maturation and T-cell activation in vitro. The results indicated that the drug did not interfere with these processes. Moreover, in vivo experiments demonstrated that the drug promoted the infiltration of dendritic cells and, to a lesser extent, T-cells into the tumor microenvironment.

However, the drug did not sensitize tumor cells to programmed cell death-1 (PD-1) inhibition, which is a common immunotherapy approach. Instead, the drug enhanced the therapeutic efficacy of TCR-redirected T-cell therapy and dendritic cell vaccination. These treatments collectively increased the overall survival of mice with B16-OVA melanoma tumors.

Overall, the findings of this study support the concept of methylation-targeted epigenetic reprogramming as a potential strategy for treating melanoma. Dual inhibition of G9a and DNMTs may help shift the cancer-immune set-point towards responsiveness to active and adoptive vaccination against melanoma. This research suggests that combination therapies targeting epigenetic modifications could be a promising approach to improving the treatment outcomes for malignant melanoma, although further studies and clinical trials would be needed to validate these findings in human patients.