By focusing on an enzyme that plays a key role in head and neck cancer cells, researchers from the UCLA School of Dentistry were able to significantly reduce the growth and spread of tumors in mice and add to the effectiveness of immunotherapy whether these types of cancers often become resistant.
Their findings, published online in the journal Cell molecular, it could help researchers develop more sophisticated approaches to combating aggressive squamous cell cancers of the head and neck, which specifically affect the mouth , the nose and throat.
Immunotherapy, which is used as a clinical treatment for a number of cancers, makes use of the body’s natural defenses to fight disease. But some cancers, including head and neck squamous cell carcinomas, do not respond as well to treatment as others. The prognosis for these head and neck cancers is poor, with a five-year high mortality rate, and effective treatment is urgently needed.
The UCLA research team, led by renowned professor Dr. Cun-Yu Wang, chair of oral biology at the dental school, said that by targeting vulnerabilities in the cellular process of tumor duplication and immunity, they could influence the response of tumor cells to immunotherapy.
Their target enzyme, KDM4A, is an epigenetic factor – a molecule that regulates gene expression, silences some genes in cells and activates others. In squamous cell head and neck cancers, overexpression of KDM4A stimulates gene expression associated with cancer cell reproduction and proliferation.
It is known that tumor cells can spread undetected by the immune system and, without examination, can metastasize to lymph nodes or other parts of the body. In this condition, tumor cells that develop in the epithelial layer that stretches the structures of the head and neck can turn into squamous cell carcinoma of the head and neck when not examined.
Cancer cell reproduction occurs through abnormal distribution and activation of signaling pathways for cancer cells, and the researchers asked the question: If we can stop these processes and identify vulnerabilities, the we can change the body’s response to fighting cancer cells and responding to the outside. immunotherapy?
We know that the KDM4A gene plays a vital role in cancer cell reproduction and proliferation, so we focused our study on removing this gene to see if we can find a response to it.. “
Dr. Cun-Yu Wang, Associate Research Author and Member of the Jonsson Comprehensive Cancer Center, University of California – Los Angeles
By removing the KDM4A gene in their mouse models, the researchers saw a marked reduction in squamous cell carcinomas and far less cancer metastasis to the lymph nodes – a precursor to the spread of the disease throughout bodies.
Surprisingly, they also found that removal of the KDM4A also recruited and activated T cells that fought against the body, killed cancer cells and stimulated tumor immunity. sexual.
They then sought to find out why the squamous cell carcinoma cells responded so poorly to immunotherapy treatment. In another set of mouse models, they again removed KDM4A and introduced PD-1 inhibitor, which is indicated immunotherapy drugs to attack cancer cells. The combination of immunotherapy and KDM4A removal further reduced squamous cell cancer growth and lymph node metastasis.
Next, the researchers tested whether a small-molecule inhibitor of KDM4A could increase the effectiveness of the original blockade-based immunotherapy PD-1. They found that the inhibitor significantly helped in the removal of cancer stem cells, which are associated with cancer recurrence.
The findings promise the development of more specific protectors for KDM4A and more effective cancer immunotherapies.
“Dr. Cun-Yu Wang and his team are constantly influencing me through breaking through barriers in our understanding of cancer-causing cellular processes,” said Dr. Paul Krebsbach, dean and senior at the UCLA School of Dentistry. “The results of this study have a significant impact on the development of more effective and life-saving cancer treatments.”
Source:
University of California – Los Angeles
Magazine Reference:
Zhang, W., et al. (2021) Targeting KDM4A actively activates tumor-cell-mediated immunity by stimulating DNA replication stress. Cell molecular. doi.org/10.1016/j.molcel.2021.02.038.