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cGAS-STING pathway expression correlates with genomic instability and immune cell infiltration in breast cancer
Mengting Chen1, Shibo Yu2, Tineke van der Sluis2
1Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Abstract:
Genomic instability, as caused by oncogene-induced replication stress, 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 also with favorable response to treatment, including to immune checkpoint inhibition. In this study, we aim to explore relations between inflammatory signaling, markers of replication stress, and immune cell infiltration in breast cancer. Expression levels of cGAS-STING signaling components (STING, phospho-TBK1, and phospho-STAT1), replication stress markers (γH2AX and pRPA), replication stress-related proto-oncogenes (Cyclin E1 and c-Myc) and immune cell markers (CD20, CD4, and CD57) are determined immunohistochemically on primary breast cancer samples (n = 380). RNA-sequencing data from TCGA (n = 1082) and METABRIC (n = 1904) are used to calculate cGAS-STING scores. pTBK1, pSTAT1 expression and cGAS-STING pathway scores are all increased in triple-negative breast cancers compared to other subtypes. Expression of γH2AX, pRPA, Cyclin E1, c-Myc, and immune cell infiltration positively correlate with p-STAT1 expression (P < 0.001). Additionally, we observe significant positive associations between expression of pTBK1 and γH2AX, pRPA, c-Myc, and number of CD4+ cells and CD20+ cells. Also, cGAS-STING scores are correlated with genomic instability metrics, such as homologous recombination deficiency (P < 0.001) and tumor mutational burden (P < 0.01). Moreover, data from the I-SPY2 clinical trial (n = 71) confirms that higher cGAS-STING scores are observed in breast cancer patients who responded to immunotherapy combined with chemotherapy. In conclusion, the cGAS-STING pathway is highly expressed in TNBCs and is correlated with genomic instability and immune cell infiltration.
Insights
Genomic instability and replication stress activate inflammatory signaling via the cGAS-STING pathway in breast cancer. This pathway correlates with immune cell infiltration and predicts response to immunotherapy in triple-negative breast cancers.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Genomic instability, driven by oncogene-induced replication stress, can activate inflammatory signaling pathways like cGAS-STING and JAK-STAT.
- While inflammatory signaling is linked to tumor progression, it also correlates with favorable treatment responses, including immune checkpoint inhibition.
Purpose of the Study:
- To investigate the relationships between inflammatory signaling, replication stress markers, and immune cell infiltration in breast cancer.
- To analyze the expression of cGAS-STING pathway components, replication stress markers, and immune cell markers in breast cancer samples.
Main Methods:
- Immunohistochemistry was used to assess STING, phospho-TBK1 (pTBK1), phospho-STAT1 (pSTAT1), γH2AX, pRPA, Cyclin E1, c-Myc, CD20, CD4, and CD57 in 380 primary breast cancer samples.
- RNA-sequencing data from TCGA (n=1082) and METABRIC (n=1904) were utilized to compute cGAS-STING pathway scores.
- Associations between these markers, genomic instability metrics, and clinical response data from the I-SPY2 trial (n=71) were analyzed.
Main Results:
- Increased pTBK1, pSTAT1 expression, and cGAS-STING pathway scores were observed in triple-negative breast cancers (TNBCs) compared to other subtypes.
- Expression of replication stress markers (γH2AX, pRPA), proto-oncogenes (Cyclin E1, c-Myc), and immune cell infiltration positively correlated with pSTAT1 expression.
- cGAS-STING pathway scores correlated with genomic instability markers (homologous recombination deficiency, tumor mutational burden) and were higher in TNBC patients who responded to immunotherapy.
Conclusions:
- The cGAS-STING pathway is significantly upregulated in triple-negative breast cancers.
- Activation of the cGAS-STING pathway is associated with increased genomic instability and immune cell infiltration in breast cancer.
- Higher cGAS-STING pathway activity predicts a favorable response to immunotherapy in combination with chemotherapy.
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