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

Abstract

Background Stimulator of interferon (IFN) genes (STING) is a protein that promotes type I IFN production essential for T‐cell activation. In this study, we aim to characterize STING expression comprehensively using The Cancer Genome Atlas (TCGA) database, cell lines, and patient tumor samples stained with immunohistochemistry. Methods Two cohorts were evaluated comprising 721 non–small cell lung cancer (NSCLC) patients and 55 NSCLC cell lines for STING and cyclic GMP‐AMP synthase (cGAS) expression using immunohistochemistry. Moreover, an independent cohort of n = 499 patients from the TCGA database was analyzed. Methylation was evaluated on STING and cGAS in five STING‐negative NSCLC cell lines. Results STING RNA expression positively correlates with T cell function and development genes, negatively correlates with cell proliferation and associated with increased survival (5‐year‐overall survival [OS] 47.3% vs. 38.8%, p = 0.033). STING protein expression is significantly higher in adenocarcinoma (AC) and is lost with increasing stages of AC. STING‐positivity is significantly higher in mutant EGFR and KRAS tumors. STING‐positive NSCLC patients identified with immunohistochemistry (H‐score > 50) have increased survival (median OS: 58 vs. 35 months, p = 0.02). Treatment of STING‐negative cell lines with a demethylating agent restores STING expression. Conclusions STING is ubiquitously expressed in NSCLC and associated with T cell function genes, AC histology, EGFR, and KRAS mutations and improved overall survival.

Prognostic Significance of STING Immunoexpression in Relation to HPV16 Infection in Patients with Squamous Cell Carcinomas of Oral Cavity and Oropharynx

“…In turn, Hayman et al [ 16 ], in a group of 52 patients with OPSCC, reported worse progression-free survival for patients with low tumor STING expression and independently stromal STING expression, both assessed by AQUA-based fluorescent analysis. There are also some papers concerning other types of tumors (non–small cell lung cancer, gastric, cervical or colorectal cancers) in which, similar to HNSCC, STING expression was related to better prognoses of patients [ 17 , 18 , 19 , 20 ].…”

STING expression is an independent prognostic factor in patients with mycosis fungoides

“…In contrast, another recent study showed that in EB virus-positive gastric cancer, STING-expressing cancer cells had better prognosis, while in EB virus-negative gastric cancer STING-expressing cancer cells had poorer prognosis 27 . In lung cancers, non-small cell lung cancer showed a better prognosis in tumors with lower STING expression, and STING-expressing tumors showed a significantly higher frequency of EGFR and KRAS mutations 28 . In contrast, STING expression was not associated with tumor size, clinical stage, or survival in colorectal cancer 29 .…”

Clinical significance of STING expression and methylation in lung adenocarcinoma based on bioinformatics analysis

“…In support of our analysis, downregulation of STING mRNA expression has been associated with a poor prognosis in stage I LUAD patients 32 . Recently, immunohistochemistry analysis revealed that STING protein levels decrease in NSCLC tissues as tumor stage increases and that low STING protein levels predict a poor prognosis 33 . Furthermore, downregulation of STING can predict adverse outcomes for gastric cancer, hepatocellular carcinoma, breast cancer, and colorectal cancer 11 , 15 , 16 .…”

“…Of note, DNA methyltransferase 1 (DNMT1) is a mediator of STING repression 35 and occupies the STING promoter region by interacting with NEAT1 to inhibit STING expression in lung cancer 12 . Recently, a report demonstrated that the demethylating agent 5'AZADC is sufficient to induce the expression of STING in NSCLC cell lines 33 . Consistent with these reports, we showed that STING was methylated in another LUAD patient cohort, and a strong negative correlation between STING expression and methylation was observed in LUAD tissues.…”