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AHR, a novel inhibitory immune checkpoint receptor, is a potential therapeutic target for chemoresistant glioblastoma

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Abstract

Purpose

This study aims to elucidate the mechanism underlying temozolomide resistance in patients with MGMT promoter hypomethylated glioblastoma, which is correlated with poor prognosis. The objective is to identify therapeutic targets and drugs suitable for temozolomide-resistant glioblastoma patients using big data analysis.

Methods

In this retrospective study, transcriptome sequencing data from 457 glioblastoma patients, multi-omics data, and single-cell sequencing data were employed to assess the expression pattern, prognostic value, and biological functions of AHR in glioblastoma. The HERB database was utilized to screen for AHR-targeted drugs for glioblastoma treatment. Validation of our findings was conducted using multiplex immunofluorescence staining of clinical samples and T cells and tumor cells co-culture models.

Results

Our findings demonstrated that patients with MGMT promoter unmethylation did not benefit from postoperative temozolomide chemotherapy due to resistance arising from DNA repair function and tumor immune response. AHR was found to be expressed in immune cells and exhibited an immunomodulatory role in glioblastoma with MGMT promoter unmethylation. AHR was identified as a potential novel inhibitory immune checkpoint receptor, serving as a therapeutic target for temozolomide-resistant glioblastoma. Furthermore, targeting AHR with Semen aesculi markedly enhanced the cytotoxic effect of T cells on glioma cells.

Conclusions

In addition to DNA repair function, the tumor immune response plays a pivotal role in temozolomide resistance of glioblastoma. Herbal compounds targeting AHR may offer an effective treatment for temozolomide-resistant glioblastoma.

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Availability of data and materials

All non-private data and raw data associated with this study can be provided upon reasonable request.

Abbreviations

AHR:

Aromatic hydrocarbon receptor

GBM:

Glioblastoma

GEPIA:

Gene expression profiling interactive analysis

GSEA:

Gene set enrichment analysis

GSVA:

Gene set variation analysis

IDH:

Isocitrate dehydrogenases

KEGG:

Kyoto Encyclopedia of Genes and Genomes

MDMs:

Monocyte-derived macrophages

MGMT:

O6-methylguanine-DNA methyltransferase

PLK2:

Polo-like kinase 2

TMZ:

Temozolomide

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Acknowledgements

The authors express their gratitude to Mr. Gengrun Li for his assistance in preparing the original manuscript.

Funding

This research was supported by grants from the National Natural Science Foundation of China (Grant no. 82004137).

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Author notes

  1. Nian Tan and Wei Zhao contributed equally to this work.

Authors and Affiliations

  1. School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, No. 10 Poyanghu Road, West Area, Tuanbo New Town, Jinghai District, Tianjin, People’s Republic of China

    Nian Tan, Wei Zhao, Yiyang Wang, Ping Li, Jianwei Liu, Zhaoying Sun, Jianming Pan, Shilin Song, Shunyao Li, Ziyi Liu & Yuhong Bian

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  1. Nian Tan
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  2. Wei Zhao
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Contributions

WZ contributed to the conceptualization, methodology, writing (review and editing), and supervision of the study. YB was responsible for data curation, methodology, writing the original draft, and supervision. NT contributed to the conceptualization, methodology, writing (review and editing), supervision, and funding acquisition. YW, PL, and JL were responsible for data curation, visualization, and software. ZS, JP, and SS participated in validation, visualization, and software development. SL and ZL contributed to validation and visualization. All authors reviewed the manuscript.

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Correspondence to Nian Tan or Yuhong Bian.

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The study was approved by the ethics committee of Tianjin University of Traditional Chinese Medicine and conducted in accordance with the principles of the Declaration of Helsinki.

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Written informed consent was obtained from all participating patients.

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432_2023_4894_MOESM1_ESM.tif

Supplementary file1 Figure S1. Study flow chart. First, the study reconfirms that MGMT promoter region unmethylation results in treatment resistance in GBM patients. Then, functional enrichment analysis reveals elevated DNA repair-related and immune-related functions in treatment-resistant GBM patients. Among immune-related functions, AHR, but not PLK2, is identified as a potential therapeutic target. Further study shows AHR enrichment in MDMs and T cells, leading to an immunosuppressive tumor microenvironment. Finally, specific AHR expression in MDMs and T cells is verified in GBM samples. Immune activation role of Semen aesculi is initially explored in co-culture models (TIF 5522 KB)

Supplementary file2 Figure S2. Patient enrollment process (TIF 8748 KB)

432_2023_4894_MOESM3_ESM.tif

Supplementary file3 Figure S3. Defining cell clusters of GBM single-cell sequencing data. (A) Cell clusters of GBM single-cell sequencing data in GSE89567. (B) Expression of marker genes in different cell clusters in GSE89567. (C) Cell clusters of GBM single-cell sequencing data in GSE84465. (D) Expression of marker genes in different cell clusters in GSE84465 (TIF 16903 KB)

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Tan, N., Zhao, W., Wang, Y. et al. AHR, a novel inhibitory immune checkpoint receptor, is a potential therapeutic target for chemoresistant glioblastoma. J Cancer Res Clin Oncol 149, 9705–9720 (2023). https://doi.org/10.1007/s00432-023-04894-w

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