Regulation of CD47 expression by interferon-gamma in cancer cells
Zi-Han YeXiaoming JiangMu‐Yang HuangYulian XuYu‐Chi ChenLuo‐Wei YuanCan-Yu HuangWei-Bang YuXiuping ChenJin‐Jian Lu
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Abstract:
The anti-phagocytosis signal, CD47, prevents phagocytosis when it interacts with signal-regulatory protein alpha (SIRPα) on macrophages. Given the vital role of CD47 in immune response, further investigation on the regulation of CD47 in tumor microenvironment is needed. Herein, we identified that interferon-gamma (IFN-γ), one of the most important cytokines in the immune and inflammatory response, up-regulated CD47 expression in cancer cells and this effect could be inhibited by the JAK1/2 inhibitor ruxolitinib, as well as siRNA-mediated silencing of JAK1, STAT1, and IRF1. The IFN-γ-induced surface expression of CD47 contributed to a stronger binding affinity to SIRPα and a decrease in phagocytosis of cancer cells by macrophages. Knockdown of JAK1, STAT1, or IRF1 by siRNA reversed the decreased phagocytosis caused by IFN-γ. Besides, analysis from TCGA revealed that IFNG had a positive correlation with CD47 in various types of cancer, which was supported by the increased surface CD47 expression after IFN-γ treatment in different types of cancer cells. The discovery of IFN-γ-induced up-regulation of CD47 in cancer cells unveils another feedback inhibitory mechanism of IFN-γ, thus providing insights into cancer immunotherapy targeting CD47.Keywords:
CD47
IRF1
<p>S1. Silencing MUC1-C downregulates IRF1 expression in TNBC cells. S2. Effects of silencing MUC1-C on TNBC cells. S3. MUC1-C is necessary for PBRM1 expression A and B. S4. MUC1-C forms a direct complex with IRF1 that activates type I and II ISGs. S5. Common genes regulated in cells silenced for MUC1, IRF1, and PBRM1. S6. Silencing MUC1-C, IRF1, and PBRM1 downregulated IDO1 and WARS in TNBC cells. S7. Silencing of MUC1-C, IRF1, and PBRM1 downregulates RIG-I and MDA5 in TNBC cells. S8. Silencing MUC1-C, IRF1, and PBRM1 downregulates ISG15 expression in TNBC cells. S9. Effects of silencing IRF1 and PBRM1 on BT-549 mammosphere formation and GO-203 treatment on the viability of olaparib-resistant MDA-MB-436RR cells. Table S1. Primers used for qRT-PCR. Table S2. Primers used for ChIP-qPCR and DNase I chromatin accessibility assays. Table S3. Common downregulated 196 DEGs in BT-549 cells with silencing of MUC1, IRF1, and PBRM1. Table S4. Overlapping IFN-pathway genes downregulated in cells with MUC1-C, PBRM1, and IRF1 silencing.</p>
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Abstract SAMHD1 is an enzyme with phosphohydrolase activity. Mutations in SAMHD1 have been linked to the development of Aicardi‐Goutières syndrome in humans. This enzyme also has the capacity to restrict HIV virus replication in macrophages. Here, we report that Samhd1 is highly expressed in murine macrophages and is regulated by proinflammatory (IFN‐γ and LPS) but not by anti‐inflammatory (IL‐4 or IL‐10) activators. The induction of Samhd1 follows the pattern of an intermediate gene that requires protein synthesis. In transient transfection experiments using the Samhd1 promoter, we found that a fragment of 27 bps of this gene, falling between −937 and −910 bps relative to the transcription start site, is required for IFN‐γ‐dependent activation. Using EMSAs, we determined that IFN‐γ treatment led to the elimination of a protein complex. Chromatin immunoprecipitation assays and siRNA experiments revealed that IRF1 is required for IFN‐γ‐ or LPS‐induced Samhd1 expression. Therefore, our results indicate that Samhd1 is stimulated by proinflammatory agents IFN‐γ and LPS. Moreover, they reveal that these two agents, via IRF1, eliminate a protein complex that may be related to a repressor, thereby, triggering Samhd1 expression.
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Gamma interferon
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CD47
Antibody opsonization
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<p>S1. Silencing MUC1-C downregulates IRF1 expression in TNBC cells. S2. Effects of silencing MUC1-C on TNBC cells. S3. MUC1-C is necessary for PBRM1 expression A and B. S4. MUC1-C forms a direct complex with IRF1 that activates type I and II ISGs. S5. Common genes regulated in cells silenced for MUC1, IRF1, and PBRM1. S6. Silencing MUC1-C, IRF1, and PBRM1 downregulated IDO1 and WARS in TNBC cells. S7. Silencing of MUC1-C, IRF1, and PBRM1 downregulates RIG-I and MDA5 in TNBC cells. S8. Silencing MUC1-C, IRF1, and PBRM1 downregulates ISG15 expression in TNBC cells. S9. Effects of silencing IRF1 and PBRM1 on BT-549 mammosphere formation and GO-203 treatment on the viability of olaparib-resistant MDA-MB-436RR cells. Table S1. Primers used for qRT-PCR. Table S2. Primers used for ChIP-qPCR and DNase I chromatin accessibility assays. Table S3. Common downregulated 196 DEGs in BT-549 cells with silencing of MUC1, IRF1, and PBRM1. Table S4. Overlapping IFN-pathway genes downregulated in cells with MUC1-C, PBRM1, and IRF1 silencing.</p>
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Listeria monocytogenes is widely used as a model to study immune responses against intracellular bacteria. It has been shown that neutrophils and macrophages play an important role to restrict bacterial replication in the early phase of primary infection in mice, and that the cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) are essential for protection. However, the involved signaling pathways and effector mechanisms are still poorly understood. This study investigated mouse strains deficient for the IFN-dependent transcription factors interferon consensus sequence binding protein (ICSBP), interferon regulatory factor (IRF)1 or 2 for their capacity to eliminate Listeria in vivo and in vitro and for production of inducible reactive nitrogen intermediates (RNI) or reactive oxygen intermediates (ROI) in macrophages. ICSBP−/− and to a lesser degree also IRF2−/− mice were highly susceptible to Listeria infection. This correlated with impaired elimination of Listeria from infected peritoneal macrophage (PEM) cultures stimulated with IFN-γ in vitro; in addition these cultures showed reduced and delayed oxidative burst upon IFN-γ stimulation, whereas nitric oxide production was normal. In contrast, mice deficient for IRF1 were not able to produce nitric oxide, but they efficiently controlled Listeria in vivo and in vitro. These results indicate that (a) the ICSBP/IRF2 complex is essential for IFN-γ–mediated protection against Listeria and that (b) ROI together with additional still unknown effector mechanisms may be responsible for the anti-Listeria activity of macrophages, whereas IRF1-induced RNI are not limiting.
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