Impact of histone deacetylase isoform on the effectiveness of immune checkpoint therapy

While multiple therapeutic options exist for melanoma, their overall responses in the majority of patients remain relatively low due to the interference of counter-regulatory mechanisms. This indicates the need to understand the underlying mechanisms and devise alternative approaches to enhance the effectiveness of melanoma therapies. Given that negative immune checkpoint (IC) molecules employ tolerance mechanisms to induce tumor immune evasion and to avoid antitumor immune responses, immune checkpoint inhibitors (ICIs) have been extensively explored for the treatment of melanoma. While initial promising antitumor responses are documented, often tumor cells develop resistance to ICIs, indicating the interference due to counter-regulatory mechanisms. We utilized genomic databases to determine the underlying mechanisms involved in decreased efficacy of ICIs. Our analyses identified increased expression of histone deacetylase 4 (HDAC4) and decreased expression of T-cell inflamed tumor microenvironment (TME) gene signatures in a cohort of melanoma patients. Further studies indicate that high HDAC4 was associated with poor prognosis and decreased immune score in ICI-treated melanoma patients. While other studies are warranted to validate the findings, these studies indicate that HDAC4 could be targeted to overcome the resistance mechanisms and improve ICI efficacy.