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Targeting TNFAIP2 induces immunogenic cell death and sensitizes glioblastoma multiforme to anti-PD-1 therapy

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Abstract

Background

The efficacy of current immunotherapeutic strategies for patients with glioblastoma multiforme (GBM) remains unsatisfactory. The purpose of this study was to investigate the correlation between tumor necrosis factor alpha-induced protein 2 (TNFAIP2) and immunogenic cell death (ICD) in GBM, and to examine the effect of TNFAIP2 knockdown and anti-PD-1 combination treatment in a mouse glioma model.

Methods

The CGGA and TCGA databases were used to explore the possible function of TNFAIP2 in GBM. Multiplex immunohistochemistry (mIHC) staining was performed to detect the immune infiltration of tissues. Western blot, quantitative real-time polymerase chain reaction (qRT-PCR), flow cytometry, and enzyme linked immunosorbent assay (ELISA) were utilized to detect the release of damage-associated molecular patterns (DAMPs) and the activation of the immune response. A mouse glioma model was applied to examine the induction of immune response.

Results

In vitro and in vivo studies demonstrated that TNFAIP2 knockdown increased the surface exposure of calreticulin (CALR), heat shock protein 70 kDa (HSP70), and heat shock protein 90 kDa (HSP90) in GBM cell lines, thereby inducing immunogenic cell death (ICD). Importantly, the study found that TNFAIP2 knockdown in combination with anti-PD-1 therapy significantly improved the overall survival of glioma in a mouse model.

Conclusions

TNFAIP2 knockdown induces ICD by downregulating TNFAIP2 in GBM. In addition, TNFAIP2 knockdown sensitized glioma to anti-PD-1 therapy. Hence, targeting TNFAIP2 alone or in combination with anti-PD-1 therapy may be a potential strategy for GBM treatment through ICD.

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Data availability

The datasets used during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We would like to thank Ms. Vikky and Mr. Xie Tao for language polishing.

Funding

This work was supported by the China Postdoctoral Science Foundation (2022M721500); the National Natural Science Foundation of China (No. 82072762); the National Natural Science Foundation of China (No. 82103668); the Medical Scientific Research Foundation of Dongguan People's Hospital under Grant (K202021).

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Author notes

  1. Chongxian Hou, Shenbao Shi and Mengjiao Gao have contributed equally to this work.

Authors and Affiliations

  1. The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, Department of Neurosurgery, Zhujiang Hospital, Southern Medical University, Industrial Road No. 253, Guangzhou, 510282, People’s Republic of China

    Chongxian Hou, Shenbao Shi, Mengjiao Gao, Jingsen Ji, Chengcheng Ma, Tianwei Wang, Taoliang Chen, Yang Liu, Jiasheng Zhong, Yaofeng Zheng & Yiquan Ke

  2. Department of Neurosurgery, Affiliated Dongguan People’s Hospital, Southern Medical University, Dongguan, 523059, People’s Republic of China

    Jing’an Ye

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Contributions

CH, JY, and YK considered and designed this study; CH, SS, MG, JJ, CM, YZ and JZ performed the experiments; All authors performed data analysis; CH, SS, MG, JJ, CM, and JZ wrote the draft; TW, TC, YL, JY, and YK revised the manuscript; CH, SS, and MG contributed equally to this work; YK is responsible for the overall content as guarantor.

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Correspondence to Jing’an Ye or Yiquan Ke.

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The authors have no conflict of interest.

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Approval of the research protocol by an Institutional Reviewer Board: Informed consent was obtained in all cases, and study protocols were approved by the Ethical Committee of Zhujiang Hospital. The animal protocols used in the present study were approved by the Animal Care and Use Committee of Southern Medical University (LAEC-2022–151) and complied with the Code of Ethics for Animal Experimentation.

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Hou, C., Shi, S., Gao, M. et al. Targeting TNFAIP2 induces immunogenic cell death and sensitizes glioblastoma multiforme to anti-PD-1 therapy. J Neurooncol 165, 79–90 (2023). https://doi.org/10.1007/s11060-023-04449-6

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