BACH1 as a potential target for immunotherapy in glioblastomas

Int Immunopharmacol. 2022 Feb;103:108451. doi: 10.1016/j.intimp.2021.108451. Epub 2021 Dec 17.

Abstract

Glioblastoma (GBM, WHO grade 4) is a highly heterogeneous and aggressive primary malignant brain tumor. BTB domain and CNC homology 1 (BACH1) is a transcription factor, and it plays an essential role in regulating tumor metastasis, tumor metabolism, and tumor stem cell self-renewal. However, its role in glioma is still unclear. In this research, we confirmed that BACH1 as an independent prognostic indicator was enriched in GBMs. BACH1 was strongly correlated with immune responses in GBMs, especially the M0 and M2 tumor-associated macrophage (TAM) mediated immune responses. GBMs with high expression of BACH1 express high levels of immune checkpoints (ICs), glioma cell-derived TAM chemokines, and M2 TAM markers. Interestingly, single cell RNA-seq analysis showed that the expression level of BACH1 in TAMs was higher than that in the other cell types in GBM. Transcriptome analysis of U87-MG cells showed that compared with the BACH1-vector U87-MG group, glioma cell-derived TAM chemokines (including monocyte chemotactic protein-1 (MCP-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and EGF) and ICs (including CD276, TIM-3, LAG3, TIGIT and LGALS9) were enriched in the BACH1-overexpressing U87-MG group. In addition, we constructed a polygenic risk scoring model and compound nomogram model based on BACH1, which might provide a reliable prognosis assessment tool for clinicians and aid in treatment decision-making in the clinic. In conclusion, this research identified that BACH1 might be a potential molecular signature for survival and immunotherapy response. GBMs with high expression of BACH1 have a stronger immunosuppressive tumor microenvironment (TME). Overexpression of BACH1 can upregulate the expression of glioma cell-derived TAM chemokines and ICs in vitro. Moreover, the risk model and nomogram model based on BACH1 can provide a reliable prognosis assessment tool. Therefore, BACH1 is a promising therapeutic target for GBMs.

Keywords: BTB and CNC homology 1 (BACH1); Glioblastoma (GBM); Immunotherapy; Transcriptome sequencing; Tumor microenvironment (TME).

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism*
  • Brain Neoplasms / diagnosis
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Cell Line, Tumor
  • Chemokines / metabolism
  • Datasets as Topic
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / diagnosis
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Humans
  • Immunotherapy / methods*
  • Macrophage Activation
  • Molecular Targeted Therapy
  • Nomograms
  • Risk
  • Survival Analysis
  • Tumor-Associated Macrophages / physiology*

Substances

  • BACH1 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • Biomarkers, Tumor
  • Chemokines