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Dicer deficiency impairs proliferation but potentiates anti-tumoral effect of macrophages in glioblastoma

Oncogene volume 41, pages 3791–3803 (2022)Cite this article

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Abstract

Glioblastoma is a lethal primary brain tumor with abundant immune-suppressive glioblastoma-associated macrophage (GAM) infiltration. Skewing immune suppressive GAMs towards an immune-activating phenotype represents a promising immunotherapeutic strategy against glioblastoma. Herein, we reported that genetic deletion of miRNA-processing enzyme Dicer in macrophages inhibited the growth of GL261 murine glioblastoma xenografts and prolonged survival of tumor-bearing mice. Single cell RNA sequencing (scRNA-seq) of the tumor-infiltrating immune cells revealed that Dicer deletion in macrophages reduced the proportion of cell-cycling GAM cluster and reprogramed the remaining GAMs towards a proinflammatory activation state (enhanced phagocytotic and IFN-producing signature). Dicer-deficient GAMs showed reduced level of cyclin-dependent kinases (CDK1 and CDK2) and increased expression of CDK inhibitor p27 Kip1, thus manifesting impaired proliferation. Dicer knockout enhanced phagocytotic activity of GAMs to eliminate GL261 tumor cells. Increased proinflammatory GAM clusters in macrophage Dicer-deficient mice actively interacted with tumor-infiltrating T cells and NK cells through TNF paracrine signaling to create a pro-inflammatory immune microenvironment for tumor cell elimination. Our work identifies the role of Dicer deletion in macrophages in generating an immune-activating microenvironment, which could be further developed as a potential immunotherapeutic strategy against glioblastoma.

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Fig. 1: Dicer deficiency increased the percentage of anti-tumoral macrophage sub-population and reduced the pro-tumoral macrophage sub-population.
Fig. 2: Macrophage Dicer deficiency inhibited the proliferation of GAM.
Fig. 3: Macrophage Dicer deficiency promoted phagocytosis.
Fig. 4: Macrophage Dicer deficiency inhibited the anti-inflammatory molecules, and promoted the expression of pro-inflammatory molecules on GAM.
Fig. 5: Deletion of macrophage Dicer enriched a TNF-TNFR mediated crosstalk between GAM and T- /NK- cells in GBM microenvironment.
Fig. 6: Dicer regulates GAM proliferation and phagocytosis by miR-24-3p and miR142-3p.
Fig. 7: Knockout Dicer in GAMs enhanced the therapeutic efficacy of TMZ on GBM.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China under Grants [Nos. 81821003, 81702940 and 81922056], the National Key Research and Development Program of China (2016YFA0502201), and Science and Technology Innovation Project of Chongqing Science and Technology Commission, China (No. cstc2021yszx-jcyj0003).

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  1. Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, China

    Yu-Qi Liu, Min Luo, Yu Shi, Ying Guo, Hua Zhang, Kai-Di Yang, Tian-Ran Li, Liu-Qing Yang, Qing Liu, Zhi-Cheng He, Xiao-Ning Zhang, Wen-Ying Wang, Shuai Wang, Hui Zeng, Qin Niu, Xia Zhang, You-Hong Cui, Xiu-Wu Bian & Yi-Fang Ping

  2. Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, 400038, China

    Yu-Qi Liu, Min Luo, Yu Shi, Ying Guo, Hua Zhang, Kai-Di Yang, Tian-Ran Li, Liu-Qing Yang, Qing Liu, Zhi-Cheng He, Xiao-Ning Zhang, Wen-Ying Wang, Shuai Wang, Hui Zeng, Qin Niu, Xia Zhang, You-Hong Cui, Xiu-Wu Bian & Yi-Fang Ping

  3. Army 953 Hospital, Shigatse Branch of Xinqiao Hospital, Third Military Medical University (Army Medical University), Shigatse, 857000, China

    Yu-Qi Liu

  4. Institute of Immunology, Third Military Medical University (Army Medical University), Chongqing, 400038, China

    Ting-Ting Liu, Bo Huang & Zhi-Ren Zhang

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Contributions

Conception and design: X-WB, Y-FP, Z-RZ, XZ and Y-HC. Cell culturing: Y-QL, ML and HZ. Staining: Y-QL, ML, T-TL, BH, QL and Z-CH. Immune blotting: ML, HZ, X-NZ and W-YW. Animal experiments: Y-QL, ML, HZ and SW. PCR: Y-QL and QN. Analysis of data: Y-QL, YG, K-DY and T-RL. Writing of the manuscript: Y-FP, YS and Y-QL.

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Correspondence to Zhi-Ren Zhang, Xiu-Wu Bian or Yi-Fang Ping.

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Liu, YQ., Luo, M., Shi, Y. et al. Dicer deficiency impairs proliferation but potentiates anti-tumoral effect of macrophages in glioblastoma. Oncogene 41, 3791–3803 (2022). https://doi.org/10.1038/s41388-022-02393-9

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