The clinical and molecular significance associated with STING signaling in breast cancer

Parkes, Eileen; Humphries, Matthew P.; Gilmore, Elaine S.; Sidi, Fatima Abdullah; Bingham, Victoria; Phyu, Su Myat; Craig, Stephanie G.; Graham, Catherine; Miller, Jim J.; Griffin, Daryl; Salto-Tellez, Manuel; Madden, Stephen F.; Kennedy, Richard D.; Bakhoum, Samuel F.; McQuaid, Stephen; Buckley, Niamh E.

doi:10.1038/s41523-021-00283-z

Cited by 30 publications

(21 citation statements)

References 65 publications

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“…However, pSTAT1 was not an independent prognostic marker in multivariate analysis. A previous study revealed that pnSTING is an independent predictor of favourable RFS in ER + breast cancer and is associated with immune cell in ltration and upregulation of immune checkpoints 15 .…”

Section: Discussionmentioning

confidence: 98%

“…The H scores (range from 0-200) were calculated by intensity (negative: 0; medium: 1; high: 2) multiplied by the percentage of cells in each group. As previously described, peri-nuclear STING (pnSTING) expression was evaluated by the percentage of positive cells as a proxy for activated STING 15 . The percentage of pnSTING-positive tumor cells was then scored semi-quantitatively.…”

Section: Immunohistochemistry (Ihc)mentioning

confidence: 99%

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Expression of the cGAS-STING pathway is associated with high levels of genomic instability and immune cell infiltration in breast cancer

Chen

Shao

Sluis

et al. 2023

Preprint

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Genomic instability is a hallmark of cancer, and can be caused by oncogene-induced replication stress. Besides driving the evolution of cancer genomes, genomic instability can lead to the activation of inflammatory signaling, involving the cGAS-STING and JAK-STAT pathways. Inflammatory signaling has been associated with pro-tumorigenic features, but has also been associated with favorable response to treatment, including to immune checkpoint inhibitors. To improve our understanding of the relations between genomic instability and to ultimately guide patient selection for treatment, we investigated the cGAS-STING pathway in relation to markers of replication stress and immune cell infiltration in breast cancer. Immunohistochemistry was performed to determine the expression of cGAS-STING signaling components (STING, phospho-TBK1, and phospho-STAT1), replication stress markers (γH2AX and phospho-RPA32), replication stress-related oncogenes (Cyclin E1 and c-Myc) and immune cell markers (CD20, CD4, and CD57) on primary breast cancer samples (n = 380). Clinical data and mRNA expression data from two public breast cancer databases (TCGA and METABRIC) and an immune therapy trial (I-SPY2) were used to investigate the correlation between cGAS-STING pathway activation, genomic instability markers and patient response to immune therapy. We find that phospho-TBK1, and phospho-STAT1 were highly expressed in triple-negative breast cancers (TNBCs). In addition, expression of genomic instability markers γH2AX and pRPA, replication stress-related oncogenes Cyclin E1 and c-Myc, and immune cell markers were all positively correlated with phospho-STAT1 expression (P < 0.001). We also found that phospho-TBK1 was positively associated with γH2AX (P < 0.002), c-Myc (P < 0.001), CD4 (P < 0.001) and CD20 (P < 0.05). Besides, a positive correlation between perinuclear STING and CD4 was observed (P < 0.01). Accordingly, cGAS-STING pathway components also showed the highest expression levels in TNBCs in both TCGA and METABRIC cohorts. Also, cGAS-STING scores were significantly positively correlated with metrics of genomic instability, including homologous recombination deficiency (HRD) (TCGA: r = 0.296, P < 0.001) and tumor mutational burden (TMB) (TCGA: r = 0.254, P < 0.001; METABRIC: r = 0.0632, P < 0.01). Moreover, higher expression of the cGAS-STING score was also observed in patients who responded to immunotherapy. In conclusion, our study shows that the cGAS-STING pathway is highly expressed in TNBCs, and is positively correlated with genomic instability and immune cell infiltration.

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Section: Discussionmentioning

confidence: 98%

Section: Immunohistochemistry (Ihc)mentioning

confidence: 99%

Expression of the cGAS-STING pathway is associated with high levels of genomic instability and immune cell infiltration in breast cancer

Chen

Shao

Sluis

et al. 2023

Preprint

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“…Conversely, STING activation of noncanonical inflammatory pathways has been found to promote epithelial–mesenchymal transition and metastasis in cancers with high chromosomal instability that generate excessive dsDNA in the cytosol ( 74 ). It is possible that evasion or activation of dsDNA sensing pathways in tumors is largely shaped by specific tumor contexts, selective pressures, and immune editing that are not captured by reductionist models ( 48 , 69 , 70 , 75 , 76 , 77 , 78 ). Our work demonstrates that separate from specific tumor or immune selective factors, oncogenes autonomously downregulate T1IFN expression, causing direct and dramatic consequences to antiviral dsRNA sensors that are strong ISGs.…”

Section: Discussionmentioning

confidence: 99%

Discovery Proteomics Analysis Determines That Driver Oncogenes Suppress Antiviral Defense Pathways Through Reduction in Interferon-β Autocrine Stimulation

Solomon¹,

Kirkemo²,

Wilson³

et al. 2022

Molecular & Cellular Proteomics

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“…Compared to control (Ctr) cells, loss of Atg5 in ECs increased granular STING staining in the perinuclear regions, a hallmark of STING activation and signaling (Extended Data Fig. 4h) 40 .…”

Section: Autophagy Blunts the Nf-b And Cgas-sting Inflammatory Axis ...mentioning

confidence: 97%

Tumor Endothelial Cell Autophagy Is a Key Vascular-Immune Checkpoint in Melanoma

Verhoeven

Jacobs

Rizzollo

et al. 2023

Preprint

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Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune-excluded tumor phenotype. However, the molecular mechanisms that sustain TEC-mediated immunosuppression remain largely elusive. Here, we show that autophagy ablation in TECs boosts antitumor immunity by supporting infiltration and effector function of T cells, thereby restricting melanoma growth. In melanoma-bearing mice, loss of TEC autophagy leads to the transcriptional expression of an immunostimulatory/inflammatory TEC phenotype driven by heightened NF-kB and STING signaling. In line, single-cell transcriptomic datasets from melanoma patients disclose an enriched InflammatoryHigh/AutophagyLow TEC phenotype in correlation with clinical responses to immunotherapy. Congruently, patients responding to immunotherapy exhibit an increased presence of inflamed vessels, interfacing with infiltrating CD8+ T cells. Mechanistically, STING-dependent immunity in TECs is not critical for the immunomodulatory effects of autophagy ablation, since NF-kB-driven inflammation remains functional in STING/ATG5 double knockout TECs. Hence, autophagy is a principal tumor vascular anti-inflammatory mechanism dampening melanoma antitumor immunity.

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The clinical and molecular significance associated with STING signaling in breast cancer

Cited by 30 publications

References 65 publications

Expression of the cGAS-STING pathway is associated with high levels of genomic instability and immune cell infiltration in breast cancer

Expression of the cGAS-STING pathway is associated with high levels of genomic instability and immune cell infiltration in breast cancer

Discovery Proteomics Analysis Determines That Driver Oncogenes Suppress Antiviral Defense Pathways Through Reduction in Interferon-β Autocrine Stimulation

Tumor Endothelial Cell Autophagy Is a Key Vascular-Immune Checkpoint in Melanoma

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