Many cancers have experienced remarkable positive clinical effects from immunotherapies, especially when they are combined with chemotherapy. However, some cancers respond poorly to immunotherapy and ovarian cancer is one of the most resistant. The latest study from researchers at The Wistar Institute, a biomedical research leader in the fields of immunology, cancer infectious disease, and vaccine development, identifies two genes that play a critical role in protecting ovarian cancer against the immune system.
These findings were published in Cancer Immunology Research by the American Association for Cancer Research. They could lead to the creation of new treatments that make ovarian cancer and other types of cancer more susceptible to immunotherapy.
“Ovarian cancer has a relatively poor response to immunotherapy in comparison to other forms of cancers, like the melanoma and non-small-cell lung cancer,” says Rugang Zhang, Ph.D., deputy director of the Cancer Center, Christopher M. Davis Endowed Professor and program leader of the Immunology, Microenvironment & Metastasis Program at The Wistar Institute. “But we are still seeking immunotherapy, so we must find a new strategy.”
The study researchers employed CRISPR screening, a tool that allows scientists to scan through a large group of genes to determine which ones perform a specific function. Through a test of genes extracted from ovarian cancer cells of mice they found genes that encode the SETDB1-TRIM28 protein as playing a key role in suppressing the immune system.
The researchers then examined the genetic information of patients suffering from human ovarian cancer and discovered that these genes were associated negatively with immune profiles. This suggests that patients who had more of these genes were more likely to be resistant to immunotherapy.
The study found that the complex is over-expressed in many types and types of cancers, including the ovarian cancer. It’s also present in as high as 25 percent of patients. These results could lead to new treatments that target the complex and boost the effectiveness of immunotherapies against resistance cancers, including ovarian.
First author Jianhuang Lin, Ph.D. Postdoctoral fellow in the Zhang Laboratory, noted that there are already drugs that broadly target the kind of enzyme that interacts with the immune-suppressing complex. The drugs can be modified to target specifically the SETDB1-TRIM28 enzyme.
There are many histone methyltransferase inhibitors currently in development, but none are currently being tested against this specific target. Since our discovery is new, it holds promise for creating new combination immunotherapies for cancer of the ovary.”
Jianhuang Lin, Ph.D., First Author
New treatments for ovarian cancer could also be available to patients with other types cancers.
The Zhang lab will now explore how to best target this newly discovered compound to boost anti-tumor immunity.
Lin, J., et. al. (2021). The SETDB1–TRIM28 Complex inhibits anti-tumor immunity. Cancer Immunology Research. doi.org/10.1158/2326-6066.CIR-21-0754.
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