IFNγ-Induced Bcl3, PD-L1 and IL-8 Signaling in Ovarian Cancer: Mechanisms and Clinical Significance
<p>Schematic illustration of cellular sources and targets of IFNγ in OC TME. In addition to tumor-infiltrating lymphocytes (TILs), IFNγ can be produced by tumor-associated macrophages (TAMs) and monocytic cells (Monos) present in TME. The cellular targets of the produced IFNγ include OC cells and also TILs, TAMs, dendritic cells (DCs), myeloid-derived suppressor cells (MDSCs), as well as cancer-associated fibroblasts (CAFs). Created with BioRender.com with granted permission and license.</p> "> Figure 2
<p>Schematic illustration of the mechanisms regulating IFNγ-induced Bcl3, PD-L1 and IL-8 expression in OC cells. IFNγ binds to its receptors IFNGR1 and IFNGR2, resulting in the activation of JAK1 kinase, and increased expression of the transcription regulators IRF1, STAT1, p65 NFκB and Bcl3 in OC cells [<a href="#B47-cancers-16-02676" class="html-bibr">47</a>,<a href="#B49-cancers-16-02676" class="html-bibr">49</a>,<a href="#B50-cancers-16-02676" class="html-bibr">50</a>]. JAK1 phosphorylates STAT1 at Tyr-701, which is required for the nuclear translocation of STAT1. STAT1 is then phosphorylated at Ser-727, which promotes its recruitment to the Bcl3, PD-L1 and IL-8 promoters. In addition, IFNγ induces p300-mediated acetylation of p65 NFκB at K314/315, resulting in increased p65 transcriptional activity and recruitment to PD-L1 and IL-8 promoters [<a href="#B47-cancers-16-02676" class="html-bibr">47</a>,<a href="#B49-cancers-16-02676" class="html-bibr">49</a>]. IFNγ also induces acetylation of histones (Ac) at the Bcl3, PD-L1 and IL-8 promoters in OC cells, thus facilitating transcription factor recruitment and transcription [<a href="#B47-cancers-16-02676" class="html-bibr">47</a>,<a href="#B48-cancers-16-02676" class="html-bibr">48</a>,<a href="#B49-cancers-16-02676" class="html-bibr">49</a>,<a href="#B50-cancers-16-02676" class="html-bibr">50</a>,<a href="#B51-cancers-16-02676" class="html-bibr">51</a>]. Created with BioRender.com with granted permission and license.</p> "> Figure 3
<p>Bcl3 tumor-promoting functions in ovarian cancer. By inducing the expression of ceruloplasmin [<a href="#B96-cancers-16-02676" class="html-bibr">96</a>] and IL-8 [<a href="#B50-cancers-16-02676" class="html-bibr">50</a>,<a href="#B51-cancers-16-02676" class="html-bibr">51</a>], Bcl3 promotes proliferation, invasion and angiogenesis in OC cells. By inducing the expression of PD-L1 [<a href="#B47-cancers-16-02676" class="html-bibr">47</a>,<a href="#B49-cancers-16-02676" class="html-bibr">49</a>], Bcl3 also promotes immune escape in ovarian cancer. Created with BioRender.com.</p> "> Figure 4
<p>Mechanisms inducing IL-8 expression in ovarian cancer and the tumor promoting effects of IL-8 in OC cells.</p> "> Figure 5
<p>Bcl3, PD-L1 and IL-8 co-expression in ovarian cancer tissues. (<b>A</b>) Heatmap of Bcl3, PD-L1/CD274 and IL-8/CXCL8 mRNA co-expression in 379 OC samples in the GDC-TCGA database using the UCSC Xena platform. (<b>B</b>) Scatter plots showing associations between Bcl3 and PD-L1/CD274, between Bcl3 and IL-8/CXCL8 and between IL-8/CXCL8 and PD-L1/CD274 gene expression in GDC-TCGA ovarian cancer samples (<span class="html-italic">n</span> = 379) using the UCSC Xena browser.</p> "> Figure 6
<p>Model of how IFNγ induces Bcl3-dependent IL-8 and PD-L1 expression in OC cells. IFNγ induces first the expression of Bcl3 in OC cells, resulting in increased transcription of IL-8 and PD-L1. The increased expression of IL-8 and PD-L1 enhances OC cell proliferation, migration, invasion, epithelial-to-mesenchymal transition (EMT), metastasis, angiogenesis, cell stemness and immune escape.</p> ">
Abstract
:Simple Summary
Abstract
1. Introduction
2. IFNγ Signaling in Ovarian Cancer
3. Bcl3 in Ovarian Cancer
3.1. Bcl3 Signaling
3.2. Bcl3 Expression and Function in OC
3.3. Mechanisms Regulating IFNγ-Induced Bcl3 Expression in OC
4. PD-L1 in Ovarian Cancer
4.1. PD-L1 Signaling
4.2. PD-L1 Expression and Function in OC
4.3. Mechanisms Regulating IFNγ-Induced PD-L1 Expression in OC
5. IL-8 in Ovarian Cancer
5.1. IL-8 Signaling
5.2. IL-8 Expression and Function in OC
5.3. Mechanisms Regulating IFNγ-Induced IL-8 Expression in OC
6. Bcl3, PD-L1 and IL-8 Co-Expression in Ovarian Cancer
6.1. Genomic Studies in OC
6.2. Mechanisms Regulating Bcl3, PD-L1 and IL-8 Co-Expression in OC
7. Targeting IFNγ-Induced Bcl3, PD-L1 and IL-8 Expression
7.1. Targeting Bcl3 in OC
7.2. Targeting PD-L1 in OC
7.3. Targeting IL-8 in OC
7.4. Clinical Studies Based on Simultaneous Inhibition of IL-8 and PD-1/PD-L1 Signaling
8. Conclusions and Perspectives
Author Contributions
Funding
Data Availability Statement
Conflicts of Interest
References
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IFNγ Antitumor Functions | IFNγ Tumorigenic Functions |
---|---|
Increased MHC expression [22,23] | Increased CA125 expression [45] |
Increased T-cell migration [24] | Increased HLA-E expression [46] |
Increased OC cell apoptosis [25,26] | Increased PD-L1 expression [36,38,47,48,49] |
Decreased HER2 expression [27] | Increased Bcl3 expression [47,50] |
Increased tumor cell lysis [28,29] | Increased IL-8 expression [50,51] |
Reference | Combination Therapy | Disease | Phase |
---|---|---|---|
NCT03400332 | BMS-986253 + Nivolumab | Melanoma and advanced cancers | I/II |
NCT04572451 | BMS-986253 + Nivolumab | Melanoma and advanced cancers | I |
NCT04050462 | BMS-986253 + Nivolumab | Hepatocellular carcinoma | II |
NCT03689699 | BMS-986253 + Nivolumab | Prostate cancer | I/II |
NCT02451982 | BMS-986253 + Nivolumab | Pancreatic cancer | II |
NCT04848116 | BMS-986253 + Nivolumab | Head and neck carcinoma | II |
NCT03026140 | BMS-986253 + Nivolumab | Colon carcinoma | II |
NCT03161431 | SX-682 + Pembrolizumab | Metastatic melanoma | I |
NCT04599140 | SX-682 + Nivolumab | Metastatic colorectal cancer | I/II |
NCT06149481 | SX-682 + Retifanlimab | Metastatic colorectal cancer | I/II |
NCT05604560 | SX-682 + Tislelizumab | Pancreatic adenocarcinoma | II |
NCT04477343 | SX-682 + Nivolumab | Pancreatic adenocarcinoma | I |
NCT05570825 | SX-682 + Pembrolizumab | Non-small-cell lung cancer | II |
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Reddy, S.U.; Sadia, F.Z.; Vancura, A.; Vancurova, I. IFNγ-Induced Bcl3, PD-L1 and IL-8 Signaling in Ovarian Cancer: Mechanisms and Clinical Significance. Cancers 2024, 16, 2676. https://doi.org/10.3390/cancers16152676
Reddy SU, Sadia FZ, Vancura A, Vancurova I. IFNγ-Induced Bcl3, PD-L1 and IL-8 Signaling in Ovarian Cancer: Mechanisms and Clinical Significance. Cancers. 2024; 16(15):2676. https://doi.org/10.3390/cancers16152676
Chicago/Turabian StyleReddy, Suprataptha U., Fatema Zohra Sadia, Ales Vancura, and Ivana Vancurova. 2024. "IFNγ-Induced Bcl3, PD-L1 and IL-8 Signaling in Ovarian Cancer: Mechanisms and Clinical Significance" Cancers 16, no. 15: 2676. https://doi.org/10.3390/cancers16152676