Researchers at the University of California San Diego School of Medicine and UC San Diego Moores Cancer Center, with collaborators at the La Jolla Institute of Immunology and elsewhere in the United States, have further elucidated how tumors of ovarian cancer defy immunotherapy, identifying new molecular targets that could enhance the immune response, as published in the magazine ‘PNAS’.
Ovarian cancer is the fifth leading cause of cancer death among women and most of these cases are high-grade serous ovarian cancer tumorsaccording to the American Cancer Society.
High-grade serous ovarian cancer is fatal in part because It is usually resistant to chemotherapy. Immunotherapy, a therapeutic approach that uses a person’s immune system to fight disease, has shown promise in many types of cancer, but approaches using immunotherapy have not yet shown success in this type of tumor.
One approach to immunotherapy targets proteins called checkpoint receptors that They act as brakes on the activation of the immune system. Checkpoint receptor inhibitors release this brake, allowing the immune system to attack cancer cells. However, for immunotherapy to work effectively against this tumor, the treatments also have to deactivate the protective environment created by the cancer cells.
In the study led by Duygu Ozmadenci, MD, postdoctoral fellow, and lead author David D. Schlaepfer, MD, professor in the Department of Obstetrics, Gynecology, and Reproductive Sciences at the University of California, San Diego School of Medicine , provide new insights into the molecular details of communication between tumor and immune cells and the resulting dysfunction in high-grade serous ovarian cancer.
“Ovarian cancer is one of the biggest challenges in oncology,” says Schlaepfer. “Tumors can develop without obvious symptoms. The most common sign of ovarian cancer is abdominal swelling when the disease is advanced, which is when most women are diagnosed.
Ozmadenci and colleagues found that activation of a key signaling protein within tumors called focal adhesion kinase (FAK) regulated the expression of a protein called CD155 that binds to a checkpoint receptor called TIGIT on cells immune. In effect, the tumor builds a safe environment for cancer cells to grow and evade immune detection, in part maintaining high levels of CD155 as a shield against immune attack.
In a preclinical model of aggressive ovarian cancer, the researchers found that an oral anti-FAK drug reduced CD155 and other checkpoint proteins. When used together with an immunotherapy that blocked TIGIT, an increased immune response against ovarian cancer cells was seen. This, in turn, led to smaller tumors and longer survival.
“Several companies are testing FAK inhibitors and others have TIGIT checkpoint receptor inhibitory antibodies in clinical trials,” Schlaepfer says. “In high-grade serous ovarian cancer, where elevated levels of CD155 and active FAK are common, Our results provide compelling support for targeting FAK and TIGIT as part of a novel immune-boosting therapeutic strategy.”
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