cGAS-STING pathway expression as a prognostic tool in NSCLC

Abstract

Background: Disease recurrence in localized lung adenocarcinoma is a major obstacle for improving the overall outcome of lung cancer. Thus, better prognostic biomarkers are needed to identify patients at risk. In order to clear cancer, immune detection of tumor cells is of vital importance. DNA-leakage into the cytosol and tumor environment is one important tumor-associated danger signal and cGAS is a pivotal DNAsensor that detects misplaced DNA and initiates an innate immune response. In this study, we investigate the cGAS-STING-pathway expression in tumor tissue and circulating immune cells from lung adenocarcinoma patients in relation to stage of disease and overall survival (OS).Methods: Gene expression was measured using target specific droplet digital polymerase chain reaction (ddPCR) assays in a cohort of 80 patients with lung adenocarcinoma and 45 patients suspected of lung cancer, but determined to be cancer-free. The expression values were correlated to stage of disease. For further exploration of stage dependent expression, we used a publicly available gene expression data set to stratify patients by stage and correlate gene expression to OS. Results:In both tumor tissue and peripheral blood mononuclear cells (PBMCs) from cancer patients, we observed differential expression of cGAS-STING pathway components compared to cancer-free individuals. Furthermore, cGAS-STING pathway expression was elevated in PBMCs from patients with localized disease (stage I and II) compared to patients with metastatic disease (stage III and IV). Survival analysis based on publicly available gene expression data sets demonstrated a superior OS for patients with localized disease and high levels of cGAS, STING and TBK1. Conclusions:The expression of the cGAS-STING pathway is stage dependent and high expression is correlated with localized adenocarcinoma. For patients with localized disease, high cGAS, STING and TBK1 expression correlated with improved OS and may be a potential biomarker for this patient subgroup.

Cancer immunotherapy strategies that target the cGAS-STING pathway

“…CTLs need to leave TDLNs and enter the tumor tissue via blood vessels in order to recognize and kill cancer cells ( 44 ). The cGAS-STING pathway-induced Type-1 interferon response drives the expression of multiple chemokines such as CXCL9, CXCL10, and CCL5, that act as chemical gradients to direct CTLs into the tumor tissue ( 45 – 47 ). IFN I signaling also increases the expression of E selectin, VCAM-1, and ICAM-1 in endothelial cells, enhances vascular permeability, and facilitates immune cell extravasation, thus enhancing the antitumor effect ( 15 ).…”

Loss of STING expression is prognostic in non–small cell lung cancer

“…The STING pathway might be defective in lung tumors that can alter responses, as reported in other cancers. Others showed that STING/cGAS expression was lost in tumor tissues; however many of these studies involve only a small number of cases 23–25 . To our knowledge, STING expression has not been extensively studied in larger patient cohorts with clinicopathological data correlation.…”

“…Others showed that STING/cGAS expression was lost in tumor tissues; however many of these studies involve only a small number of cases. 23 , 24 , 25 To our knowledge, STING expression has not been extensively studied in larger patient cohorts with clinicopathological data correlation. TCGA data analysis of STING and cGAS in AC and SCC shows that low expression of STING in adenocarcinoma, but not squamous cell carcinoma, correlates with poor survival.…”

Biomarker-Targeted Therapies in Non–Small Cell Lung Cancer: Current Status and Perspectives

“…In a study which explores the overall prognosis of NSCLC, the investigators found that high STING expression was associated with improved OS in patients with local adenocarcinoma and may be a potential biomarker for NSCLC [ 159 ].…”