Search

Simple Summary: IFNγ is a multifunctional cytokine produced not only by activated lymphocytes but also in response to cancer immunotherapies; it has both antitumor and tumor-promoting effects. In ovarian cancer cells, the tumor-promoting effects of IFNγ are mediated by increased expression of the proto-oncogene Bcl3, the immune checkpoint PD-L1 and the proinflammatory cytokine IL-8. Recent studies have shown that IFNγ induces the expression of Bcl3, which then promotes the expression of PD-L1 and IL-8 in ovarian cancer cells, resulting in their increased proliferation and migration. In this review, we summarize the recent findings on the IFNγ tumor-promoting functions and on the mechanisms by which IFNγ induces Bcl3, PD-L1 and IL-8 expression in cancer cells, with a special focus on ovarian cancer. We also highlight the importance of a better understanding of these mechanisms to optimize the development of combinatorial approaches in cancer immunotherapies. IFNγ, a pleiotropic cytokine produced not only by activated lymphocytes but also in response to cancer immunotherapies, has both antitumor and tumor-promoting functions. In ovarian cancer (OC) cells, the tumor-promoting functions of IFNγ are mediated by IFNγ-induced expression of Bcl3, PD-L1 and IL-8/CXCL8, which have long been known to have critical cellular functions as a proto-oncogene, an immune checkpoint ligand and a chemoattractant, respectively. However, overwhelming evidence has demonstrated that these three genes have tumor-promoting roles far beyond their originally identified functions. These tumor-promoting mechanisms include increased cancer cell proliferation, invasion, angiogenesis, metastasis, resistance to chemotherapy and immune escape. Recent studies have shown that IFNγ-induced Bcl3, PD-L1 and IL-8 expression is regulated by the same JAK1/STAT1 signaling pathway: IFNγ induces the expression of Bcl3, which then promotes the expression of PD-L1 and IL-8 in OC cells, resulting in their increased proliferation and migration. In this review, we summarize the recent findings on how IFNγ affects the tumor microenvironment and promotes tumor progression, with a special focus on ovarian cancer and on Bcl3, PD-L1 and IL-8/CXCL8 signaling. We also discuss promising novel combinatorial strategies in clinical trials targeting Bcl3, PD-L1 and IL-8 to increase the effectiveness of cancer immunotherapies. [ABSTRACT FROM AUTHOR]