The signature of immune-subtype specific driving transcription factors suggest potential drugs for refractory glioblastoma

Wenjin Chen; Lihua Chen; Lili Guo; Ning Liu; Tao Wu; Yajing Cheng; Pengfei Xu; Yifei Li; Xiaofang Yang; Ruxiang Xu; Baodong Chen

The signature of immune-subtype specific driving transcription factors suggest potential drugs for refractory glioblastoma

Am J Cancer Res. 2023 Apr 15;13(4):1278-1294. eCollection 2023.

Authors

Wenjin Chen^{1

2}, Lihua Chen², Lili Guo², Ning Liu³, Tao Wu¹, Yajing Cheng⁴, Pengfei Xu¹, Yifei Li¹, Xiaofang Yang¹, Ruxiang Xu², Baodong Chen¹

Affiliations

¹ Department of Neurosurgery, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center Shenzhen 518000, Guangdong, P. R. China.
² Department of Neurosurgery, Sichuan Academy of Medical Science and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China Chengdu 610072, Sichuan, P. R. China.
³ Department of Neurosurgery, The Seventh Medical Center of PLA General Hospital Beijing 100000, P. R. China.
⁴ Department of Neurology, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center Shenzhen 518000, Guangdong, P. R. China.

PMID: 37168341
PMCID: PMC10164812

Abstract

Immunocharacteristics-based typing strategies can be used to reflect the similar status of tumors. Therefore, we aimed to demonstrate whether the immune subtypes of GBM have independent prognostic efficacy and whether these subtypes can be used as clinical guidance for predicting the progression of GBM and determining drug sensitivity. In this study, we found that patients with GBM were divided into three conserved immune-related subtypes based on the infiltration level of immune cells, including immunosuppressed, moderate immunoactivity, and high immunoactivity. Regarding the relevant clinical significance, the high immunoactivity in GBM indicates the worst survival, which exhibited the highest levels of oncogenic activity, including angiogenesis, tumor-associated macrophages and tumor-associated fibroblasts, indicated worst survival. The immunosuppressive subtype of GBM was more likely to carry epidermal growth factor receptor mutations and MGMT methylation, and belong to the classical and proneural subtypes; however, but the high immunoactivity subtype was not. The immune subtype-specific transcription factors (TFs) regulatory network indicates that specific TFs drive the construction of each immune subtype, and that these subtype-specific TFs are more prone to internal TFs regulation. Furthermore, the immunosuppressed and moderate immunoactivity subtypes were significantly correlated with the drugs sensitivity, whereas the high immunoactivity subtype was not, indicating that GBMs with high immunoactivity were refractory. We also found that obatoclax mesylate, NPK76-II-72-1, gemcitabine, TAK-715 are potential drugs for the treatment of refractory GBM based on drug sensitivity models of different immune subtypes. Therefore, we demonstrated that the immune subtypes of GBM have independent prognostic efficacy and can be used as clinical guidance for predicting the progression of GBM and drug sensitivity. Most importantly, this study is expected to provide a pathway for the development of effective drugs for treatment of refractory GBM.

Keywords: Glioblastoma; drug sensitivity; immune infiltration; immune subtypes; transcription factors.