Dendritic cells (DCs) are professional antigen-presenting cells that are traditionally divided into two distinct subsets: myeloid DCs (mDCs) and plasmacytoid DCs (pDCs). pDCs are known for their ability to secrete large amounts of cytokine type I interferons (IFN- α). In our previous work, we have demonstrated that pDC infiltration promotes glioblastoma (GBM) tumor immunosuppression through decreased IFN-α secretion via TLR-9 signaling and increased suppressive function of regulatory T cells (Tregs) via increased IL-10 secretion, resulting in poor overall outcomes in mouse models of GBM. Further dissecting the overall mechanism of pDC-mediated GBM immunosuppression, in this study, we identified CCL21 as highly upregulated by multiple GBM cell lines, which recruit pDCs to tumor sites via CCL21-CCR7 signaling. Furthermore, pDCs are activated by CCL21 in the GBM microenvironment through intracellular signaling of β-arrestin and CIITA. Finally, we found that CCL21-treated pDCs directly suppress CD8+ T cell proliferation without affecting regulatory T cells (Tregs) differentiation, which is considered the canonical pathway of immunotolerant regulation. Taken together, our results show that pDCs play a multifaced role in GBM immunosuppression, and CCL21 could be a novel therapeutic target in GBM to overcome pDC-mediated immunosuppression.
树突状细胞是专职抗原提呈细胞，传统上分为两个不同亚群：髓样树突状细胞和浆细胞样树突状细胞。浆细胞样树突状细胞以分泌大量I型干扰素（IFN-α）的能力而著称。我们前期研究发现，在胶质母细胞瘤小鼠模型中，浆细胞样树突状细胞浸润通过TLR-9信号通路减少IFN-α分泌，同时通过增加IL-10分泌增强调节性T细胞的抑制功能，从而促进肿瘤免疫抑制，导致总体预后不良。为深入解析浆细胞样树突状细胞介导胶质母细胞瘤免疫抑制的整体机制，本研究首次发现多种胶质母细胞瘤细胞系中CCL21表达显著上调，并通过CCL21-CCR7信号轴募集浆细胞样树突状细胞至肿瘤部位。进一步研究发现，在胶质母细胞瘤微环境中，CCL21通过β-arrestin和CIITA的胞内信号通路激活浆细胞样树突状细胞。最终我们证实，经CCL21处理的浆细胞样树突状细胞可直接抑制CD8+ T细胞增殖，且该过程不影响调节性T细胞分化——这被认为是免疫耐受调节的经典通路。综上所述，本研究揭示浆细胞样树突状细胞在胶质母细胞瘤免疫抑制中发挥多维度作用，而CCL21可能成为克服浆细胞样树突状细胞介导免疫抑制的新型治疗靶点。
CCL21 Induces Plasmacytoid Dendritic Cell Migration and Activation in a Mouse Model of Glioblastoma
肿瘤(癌症)患者之家