Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, P.R. China.
Department of Neurology, The First Hospital of China Medical University, Shenyang, P.R. China.
Cancer Immunol Res. 2024 Mar 4;12(3):363-376. doi: 10.1158/2326-6066.CIR-23-0418.
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.
肿瘤相关巨噬细胞（TAM）的广泛浸润与髓系来源的抑制性细胞共同构成了抑制性微环境，并促进了胶质瘤的恶性表型。侵袭性间充质（MES）亚型的胶质瘤干细胞（GSC）在胶质瘤的抑制性微环境中尤为突出。然而，其潜在的免疫抑制机制尚不清楚。本研究表明，NFAT1-/- 小鼠的胶质瘤中激活了抗肿瘤免疫微环境，提示 T 细胞激活核因子 1（NFAT1）诱导了免疫抑制微环境。在 TAMs 中，NFAT1 可以上调补体 3（C3）的转录活性，并增加 C3a 的分泌，C3a 可以与 C3aR 结合，并通过激活 TIM-3 促进 M2 样巨噬细胞极化。同时，C3a/C3aR 激活 Ca2+-NFAT1 通路，为 TAMs 的 M2 样极化形成正反馈环，进一步促进 GSCs 的 MES 转化。最后，使用 C3aR 抑制剂破坏这个反馈环，显著抑制了体外和体内的胶质瘤生长。本研究表明，NFAT1-C3a-C3aR 正反馈环诱导 M2 样 TAMs，并进一步促进 GSCs 的恶性表型，这可能是治疗胶质瘤的潜在靶点。
