Head and neck squamous cell carcinomas don’t always respond well to immunotherapy as other cancers do, thus there is an urgent need for more effective treatments. Now, researchers from the University of California, Los Angeles (UCLA), report they were able to improve immunotherapy and slow tumor growth in a mouse model by targeting an enzyme that plays a key role in head and neck cancers.

Their findings are published in the journal Molecular Cell in a paper titled, “Targeting KDM4A epigenetically activates tumor-cell-intrinsic immunity by inducing DNA replication stress.”

“Developing strategies to activate tumor-cell-intrinsic immune response is critical for improving tumor immunotherapy by exploiting tumor vulnerability,” wrote the researchers. “KDM4A, as a histone H3 lysine 9 trimethylation (H3K9me3) demethylase, has been found to play a critical role in squamous cell carcinoma (SCC) growth and metastasis. Here we report that KDM4A inhibition promoted heterochromatin compaction and induced DNA replication stress, which elicited antitumor immunity in SCC.”

The researchers were led by Cun-Yu Wang, PhD, professor and chair of oral biology at the UCLA dentistry school. They focused on KDM4A, due to the fact that overexpression of KDM4A promotes gene expression associated with cancer cell replication and spread in head and neck cancers.

“We know that the KDM4A gene plays a critical role in cancer cell replication and spread, so we focused our study on removing this gene to see if we would get an opposite response,” explained Wang.

By removing the KDM4A gene in the mouse models, the researchers observed a significant decrease in squamous cell carcinomas and less metastasis of cancer to the lymph nodes. The researchers also discovered that the KDM4A’s removal also led to the recruitment and activation of the body’s infection-fighting T cells, which killed cancer cells and stimulated inherent tumor immunity.

The researchers then sought to understand the poor response to immunotherapy in squamous carcinoma cells. In another set of mouse models, they removed KDM4A and introduced a PD-1 blockade. The combination of immunotherapy and KDM4A removal further decreased squamous cell cancer growth and lymph node metastasis.

The researchers finally tested whether a small-molecule inhibitor of KDM4A could improve the efficacy of the original PD-1 blockade-based immunotherapy. They observed that the inhibitor notably helped remove cancer stem cells.

“Altogether, our results demonstrate that targeting KDM4A can activate anti-tumor immunity and enable PD1 blockade immunotherapy by aggravating replication stress in SCC cells,” concluded the researchers.

Their findings pave a way for the development of more specific inhibitors for KDM4A and more effective cancer immunotherapies.

“I am continuously impressed by Cun-Yu Wang and his team for breaking through barriers in our understanding of cancer-causing cellular processes,” said Paul Krebsbach, PhD, dean and professor at the UCLA School of Dentistry. “The results of this study have major implications for the development of more effective, life-saving cancer therapies.”

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