STING is significantly increased in high-grade glioma with high risk of recurrence

ABSTRACT

In this study, we aimed to comprehensively characterize the potential relationships among the frequently mutated genes, well-known homologous recombination repair (HRR) proteins, and immune proteins in glioma from a clinical perspective. A total of 126 surgical tissues from patients initially diagnosed with glioma were included. The genetic alterations were tested using the targeted next-generation sequencing technique. The expression of HRR proteins, immune proteins, and genetic alteration-related proteins were detected using immunostaining. Integrated analysis showed that ATRX is positively correlated with STING in high-grade glioma (HGG) with wild-type ATRX and IDH1. Then, a relapse predictive risk-scoring model was established using the least absolute shrinkage and selection operator regression algorithms. The scores based on the expression of ATRX and STING significantly predict the recurrence for glioma patients, which further predict the survival for specific subgroups, characterized with high expression of RAD51 and wild-type TERT. Moreover, STING is significantly higher in patients with high relapse risk. Interestingly, STING inhibitors and agonists both suppress the growth of HGG cells, regardless of their STING levels and STING pathway activity, whereas RAD51 inhibitor B02 is found to exclusively sensitize HGG cells with high expression of STING to temozolomide in vitro and in vivo. Overall, findings in the study not only reveal that ATRX is closely correlated with STING to drive the relapse of HGG, but also provide a STING-guided combined strategy to treat patients with aggressive gliomas. Translation of these findings will ultimately improve the outcomes for ATRX and IDH1 genomically stratified subgroups in HGG.

KEYWORDS:

• ATRX
• high-grade glioma
• IDH1
• RAD51 inhibitor
• STING
• temozolomide sensitivity

Acknowledgments

We deeply appreciate Professor Yong, Ren from the Department of Pathology, Wuhan Central Theater Command General Hospital, for collecting glioma tissue blocks and clinicopathological information. Besides, we also sincerely thank the executive director Dr. Tianhai, Ji in our department for moral support and encouragement at all times. This study was financially supported by the funds from Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine (JYZZ195, YJXKB2020013).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors’ contributions

Conception and Funding: Q.Y.; Data collection: Q.Y., M.Z.; M.L.; S.J.; C.H.; Data Analysis: Q.Y.; M.Z.; M.L.; Writing: Q.Y.; Review and final approval: All authors.

Availability of data and materials

All the datasets are presented in the main manuscript or additional supporting files wherever possible. The targeted NGS data were deposited in the National Genomics Data Center under the accession number PRJCA012429.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2024.2327682

Additional information

Funding

The work was supported by the Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine [JYZZ195].