Affiliation:
1. University Medical Center Groningen
2. University of Groningen, University Medical Center Groningen
3. Antoni van Leeuwenhoek-Netherlands Cancer Institute/University of Groningen, University Medical Center Groningen
4. UMCG
Abstract
Abstract
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.
Publisher
Research Square Platform LLC
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