BRCA-deficient Ovarian Cancer and IFITM3: a New Power Couple

Project summary

More than 14,000 patients in the United States die of ovarian cancer each year, making this cancer the fifth leading cause of cancer death among women in the United States. Within different subtypes of ovarian cancer, high-grade serous ovarian cancer (HGSC) is not only the most common type but also the deadliest. Inheritance of one defective copy of either of the two breast cancer susceptibility genes, BRCA1 and BRCA2, predisposes individuals to breast and ovarian cancers. Indeed, approximately 50% of HGSCs harbor genetic and epigenetic alterations in the BRCA1 and 2 genes, which are members of the DNA repair pathway. Interestingly, tumors that arise in BRCA carriers are likely to be more sensitive to platinum-based chemotherapy and are associated with improved survival, but the underlying mechanisms have not been well elucidated. In our preliminary studies, we discovered that BRCA-deficient tumors have increased levels of a protein named interferon induced transmembrane protein 3 (IFITM3), compared to BRCA-proficient tumors. Its altered expression has been linked to various pathologic and immune-related diseases including viral infections, inflammatory bowel disease, and cancer, but its role in the development of BRCA-deficient HGSC remains unknown. Recently, we found that high IFITM3 levels in BRCA-deficient HGSC cells correlated with higher expression of MHC I and II molecules that mediate improved immune response. Increased IFITM3 has also been shown to activate B cells and to increase B cell density which is usually associated with improved survival. Therefore, we hypothesize that increased DNA damage in BRCA-deficient HGSC cells upregulates IFITM3 expression which in turn activates T- and B-cells to kill the cancer cells. A deeper understanding of the mechanisms by which IFITM3 modulates the immune microenvironment in BRCA-deficient HGSC will provide us new treatment strategies based on up-regulating IFITM3 alone in both BRCA-deficient and -proficient HGSC, or in combination with other immune checkpoint inhibitors to improve their efficacies. Moreover, IFITM3 may also have the potential to become a novel biomarker to predict response to immunotherapies, and therefore patients can be stratified for treatment.