Reddy Suprataptha U, Sadia Fatema Zohra, Vancura Ales, Vancurova Ivana
Department of Biological Sciences, St. John's University, New York, NY 11439, USA.
Cancers (Basel). 2024 Jul 27;16(15):2676. doi: 10.3390/cancers16152676.
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.
干扰素γ（IFNγ）是一种多效性细胞因子，不仅由活化的淋巴细胞产生，也可作为对癌症免疫疗法的反应而产生，它具有抗肿瘤和促肿瘤功能。在卵巢癌细胞中，IFNγ的促肿瘤功能是由IFNγ诱导的Bcl3、程序性死亡配体1（PD-L1）和白细胞介素8/趋化因子CXCL8表达介导的，长期以来已知它们分别作为原癌基因、免疫检查点配体和趋化因子具有关键的细胞功能。然而，大量证据表明，这三个基因的促肿瘤作用远远超出了它们最初确定的功能。这些促肿瘤机制包括癌细胞增殖、侵袭、血管生成、转移、化疗耐药性和免疫逃逸增加。最近的研究表明，IFNγ诱导的Bcl3、PD-L1和IL-8表达受相同的Janus激酶1/信号转导和转录激活因子1（JAK1/STAT1）信号通路调节：IFNγ诱导Bcl3表达，然后促进卵巢癌细胞中PD-L1和IL-8的表达，导致它们的增殖和迁移增加。在这篇综述中，我们总结了关于IFNγ如何影响肿瘤微环境并促进肿瘤进展的最新发现，特别关注卵巢癌以及Bcl3、PD-L1和IL-8/CXCL8信号传导。我们还讨论了在针对Bcl3、PD-L1和IL-8的临床试验中有前景的新型联合策略，以提高癌症免疫疗法的有效性。
