National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
Research Center for Neuroscience, Taipei Medical University, Taipei, Taiwan.
Cell Death Dis. 2024 Jun 19;15(6):434. doi: 10.1038/s41419-024-06784-6.
The interaction between glioblastoma cells and glioblastoma-associated macrophages (GAMs) influences the immunosuppressive tumor microenvironment, leading to ineffective immunotherapies. We hypothesized that disrupting the communication between tumors and macrophages would enhance the efficacy of immunotherapies. Transcriptomic analysis of recurrent glioblastoma specimens indicated an enhanced neuroinflammatory pathway, with CXCL12 emerging as the top-ranked gene in secretory molecules. Single-cell transcriptome profiling of naïve glioblastoma specimens revealed CXCL12 expression in tumor and myeloid clusters. An analysis of public glioblastoma datasets has confirmed the association of CXCL12 with disease and PD-L1 expression. In vitro studies have demonstrated that exogenous CXCL12 induces pro-tumorigenic characteristics in macrophage-like cells and upregulated PD-L1 expression through NF-κB signaling. We identified CXCR7, an atypical receptor for CXCL12 predominantly present in tumor cells, as a negative regulator of CXCL12 expression by interfering with extracellular signal-regulated kinase activation. CXCR7 knockdown in a glioblastoma mouse model resulted in worse survival outcomes, increased PD-L1 expression in GAMs, and reduced CD8 T-cell infiltration compared with the control group. Ex vivo T-cell experiments demonstrated enhanced cytotoxicity against tumor cells with a selective CXCR7 agonist, VUF11207, reversing GAM-induced immunosuppression in a glioblastoma cell-macrophage-T-cell co-culture system. Notably, VUF11207 prolonged survival and potentiated the anti-tumor effect of the anti-PD-L1 antibody in glioblastoma-bearing mice. This effect was mitigated by an anti-CD8β antibody, indicating the synergistic effect of VUF11207. In conclusion, CXCL12 conferred immunosuppression mediated by pro-tumorigenic and PD-L1-expressing GAMs in glioblastoma. Targeted activation of glioblastoma-derived CXCR7 inhibits CXCL12, thereby eliciting anti-tumor immunity and enhancing the efficacy of anti-PD-L1 antibodies.
胶质母细胞瘤细胞与胶质母细胞瘤相关巨噬细胞（GAMs）之间的相互作用影响了免疫抑制性肿瘤微环境，导致免疫疗法无效。我们假设，破坏肿瘤与巨噬细胞之间的通讯将增强免疫疗法的疗效。复发性胶质母细胞瘤标本的转录组分析表明，神经炎症途径增强，趋化因子 CXCL12 作为分泌分子中排名最高的基因出现。幼稚胶质母细胞瘤标本的单细胞转录组分析显示，CXCL12 在肿瘤和髓样细胞簇中表达。对公共胶质母细胞瘤数据集的分析证实了 CXCL12 与疾病和 PD-L1 表达的关联。体外研究表明，外源性 CXCL12 通过 NF-κB 信号诱导巨噬样细胞中的促肿瘤特征，并上调 PD-L1 表达。我们发现，CXCL12 的非典型受体 CXCR7 主要存在于肿瘤细胞中，通过干扰细胞外信号调节激酶的激活，作为 CXCL12 表达的负调节剂。在胶质母细胞瘤小鼠模型中敲低 CXCR7 导致生存结果恶化，GAMs 中 PD-L1 表达增加，与对照组相比，CD8 T 细胞浸润减少。体外 T 细胞实验表明，与对照相比，用选择性 CXCR7 激动剂 VUF11207 处理可增强对肿瘤细胞的细胞毒性，逆转胶质母细胞瘤细胞-巨噬细胞-T 细胞共培养系统中 GAM 诱导的免疫抑制。值得注意的是，VUF11207 延长了荷瘤小鼠的生存时间，并增强了抗 PD-L1 抗体的抗肿瘤作用。用抗 CD8β 抗体减轻了这种作用，表明 VUF11207 具有协同作用。总之，CXCL12 赋予了胶质母细胞瘤中促肿瘤和表达 PD-L1 的 GAMs 介导的免疫抑制作用。靶向激活胶质母细胞瘤衍生的 CXCR7 可抑制 CXCL12，从而引发抗肿瘤免疫并增强抗 PD-L1 抗体的疗效。
