American Association for Cancer Research
cir-23-0418_supplementary_figure_6_supps6.pdf (185.21 kB)

Supplementary Figure 6 from An NFAT1-C3a-C3aR Positive Feedback Loop in Tumor-Associated Macrophages Promotes a Glioma Stem Cell Malignant Phenotype

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journal contribution
posted on 2024-03-04, 21:18 authored by Yaochuan Zhang, Yifu Song, Xiaoliang Wang, Mengwu Shi, Yibin Lin, Dongxia Tao, Sheng Han

The association of C5/C5aR and NFAT1 in glioma.


Foundation for Innovative Research Groups of the National Natural Science Foundation of China



Extensive infiltration by tumor-associated macrophages (TAM) in combination with myeloid-derived suppressor cells constitute the immunosuppressive microenvironment and promote the malignant phenotype of gliomas. The aggressive mesenchymal (MES)-subtype glioma stem cells (GSC) are prominent in the immunosuppressive microenvironment of gliomas. However, the underlying immune-suppressive mechanisms are still unknown. The current study showed that the antitumor immune microenvironment was activated in glioma in Nfat1−/− mice, suggesting induction of the immune-suppressive microenvironment by nuclear factor of activated T cells-1 (NFAT1). In TAMs, NFAT1 could upregulate the transcriptional activity of complement 3 (C3) and increase the secretion of C3a, which could then bind to C3aR and promote M2-like macrophage polarization by activating TIM-3. Simultaneously, C3a/C3aR activated the Ca2+-NFAT1 pathway, forming a positive feedback loop for the M2-like polarization of TAMs, which further promoted the MES transition of GSCs. Finally, disruption of this feedback loop using a C3aR inhibitor significantly inhibited glioma growth both in vitro and in vivo. The current study demonstrated that a NFAT1-C3a-C3aR positive feedback loop induces M2-like TAMs and further promotes the malignant phenotype of GSCs, which might be the potential therapeutic target for glioma.

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