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Glioma-derived ANXA1 suppresses the immune response to TLR3 ligands by promoting an anti-inflammatory tumor microenvironment

Cellular & Molecular Immunology volume 21, pages 47–59 (2024)Cite this article

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Abstract

A highly immunosuppressive tumor microenvironment (TME) and the presence of the blood‒brain barrier are the two major obstacles to eliciting an effective immune response in patients with high-grade glioma (HGG). Here, we tried to enhance the local innate immune response in relapsed HGG by intracranially injecting poly(I:C) to establish a robust antitumor immune response in this registered clinical trial (NCT03392545). During the follow-up, 12/27 (44.4%) patients who achieved tumor control concomitant with survival benefit were regarded as responders in our study. We found that the T-cell receptor (TCR) repertoire in the TME was reshaped after poly(I:C) treatment. Based on the RNA-seq analysis of tumor samples, the expression of annexin A1 (ANXA1) was significantly upregulated in the tumor cells of nonresponders, which was further validated at the protein level. In vitro and in vivo experiments showed that ANXA1 could induce the production of M2-like macrophages and microglia via its surface receptor formyl peptide receptor 1 (FPR1) to establish a Treg cell-driven immunosuppressive TME and suppress the antitumor immune response facilitated by poly(I:C). The ANXA1/FPR1 signaling axis can inhibit the innate immune response of glioma patients by promoting an anti-inflammatory and Treg-driven TME. Moreover, ANXA1 could serve as a reliable predictor of response to poly(I:C), with a notable predictive accuracy rate of 92.3%. In light of these notable findings, this study unveils a new perspective of immunotherapy for gliomas.

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Acknowledgements

This study was supported by a grant from the National Natural Science Foundation of China (81771309, 31930039 and 31821003 to Xin Lin and 82202983 to Haihui Jiang). This study was also supported by grants from the Capital’s Funds for Health Improvement and Research (2020-2-1075 to Yong Cui) and the National Key Research and Development Program of China (2019YFA0508502 to Xin Lin). The authors would like to thank Dr. Youwen He, Department of Immunology, Duke University Medical Center, for his valuable suggestions during this study.

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  1. These authors contributed equally: Yu Zheng, Haihui Jiang, Naixue Yang.

Authors and Affiliations

  1. Institute for Immunology and School of Medicine, Tsinghua University, Beijing, 100084, China

    Yu Zheng, Naixue Yang, Daosheng Huang, Lemei Jia, Jing Ling, Longchen Xu, Xun Lan & Xin Lin

  2. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, China. National Clinical Research Center for Neurological Diseases, Center of Brain Tumor, Beijing Institute for Brain Disorders and Beijing Key Laboratory of Brain Tumor, Beijing, 100070, China

    Haihui Jiang, Shaoping Shen, Mingxiao Li, Kefu Yu, Xiaohui Ren, Yong Cui & Song Lin

  3. Department of Neurosurgery, Peking University Third Hospital, Peking University, Beijing, 100191, China

    Haihui Jiang

  4. Tsinghua-Peking Center for Life Sciences, Beijing, 100084, China

    Xun Lan & Xin Lin

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  1. Yu Zheng
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Contributions

Conceptualization, XL, S., and YZ; methodology, YZ, HJ, and NY; formal analysis, YZ, HJ, and NY; investigation, YZ, HJ, NY, SS, DH, LJ., J.L and LX; resources, SL, HJ, ML, KY, XR, and YC; data curation, YZ; writing – original draft, YZ; visualization, YZ, HJ, and NY.; supervision, XL, and SL; funding acquisition, XL SL HJ, and YC.

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Correspondence to Song Lin or Xin Lin.

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Zheng, Y., Jiang, H., Yang, N. et al. Glioma-derived ANXA1 suppresses the immune response to TLR3 ligands by promoting an anti-inflammatory tumor microenvironment. Cell Mol Immunol 21, 47–59 (2024). https://doi.org/10.1038/s41423-023-01110-0

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