Targeting a specific oncogene associated with the most common type of ovarian cancer may help increase a patient’s immune response to tumors, according to recent findings from researchers at The Wistar Institute and their colleagues at University of Pennsylvania and The University of Colorado Anschutz Medical Campus.
An oncogene is a mutated version of a gene that would typically be involved in normal cell growth. The change in the gene can be either inherited or caused by environmental factors. This mutated gene or oncogene may contribute to the development of a cancerous tumor.
KDM5A is an oncogene often involved in epithelial ovarian cancer (EOC). Prior studies have shown that KDM5A is highly expressed in EOC, which is the most prevalent type of ovarian cancer. And in EOC, KMD5A is known to switch off multiple genes involved in tumor suppression.
In a promising breakthrough for targeted therapy, The Wistar Institute researchers and their colleagues have discovered that inhibiting KDM5A may help boost a patient’s immune response to tumors by restoring the function of a particular biological pathway that activates tumor-killing immune cells.
“Understanding the basic mechanism guiding the infiltration of tumor-killing immune cells into the tumor microenvironment is key to leveraging the power of the immune system to fight against cancer,” said Dr. Rugang Zhang of The Wistar Institute, who led the research. This study was made possible in part by OCRA grants to Dr. Zhang and Dr. Wei Zhou, also of The Wistar Institute. The research team additionally included OCRA grantees Dr. Jianhuang Lin of The Wistar Institute, Dr. Ronny Drapkin of University of Pennsylvania, and Dr. Benjamin Bitler of The University of Colorado Anschutz Medical Campus.
According to the team’s findings, which have been published as a research paper in Cancer Immunology Research, the KDM5A oncogene specifically represses genes involved in the biological pathway known as the antigen processing and presentation pathway. A biological pathway is an ordered series of molecular interactions in a cell that leads to a certain end point or cell function. The antigen processing and presentation pathway plays a crucial role in identifying tumor cells and activating the immune system to kill them.
“Tumor cells find a way to downregulate this antigen presentation pathway, and by doing so, they evade immune surveillance,” said Dr. Sergey Karakashev of The Wistar Institute, who co-authored the paper. “One of the main questions for this paper was, ‘How can we restore the function of the antigen presentation pathway to promote immune infiltration and immune cell activation?’” Karakashev explained.
The researchers conducted in vitro studies during which they knocked out KDM5A. When they inactivated this oncogene, the genes involved in the antigen presentation pathway were upregulated. The scientists then conducted in vivo studies using mice and mouse ovarian cancer cells that validated the findings of their in vitro experiments. When they knocked down KDM5A in the in vivo studies, the researchers saw an increase in the presence and activation of CD8+ T cells, which are immune cells that kill cancer cells. The study results also showed that KDM5A inhibition reduced the tumor burden and improved survival of tumor-bearing mice.
“Our findings provide a scientific framework to target KDM5A to overcome immune evasion employed by cancer cells,” said Dr. Zhang. “In addition to ovarian cancer, the pathway appears to be broadly applicable to many cancer types. Thus, we believe the findings are broadly applicable and may have far-reaching implications in developing cancer immunotherapy.”
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