The Fourth Section of Department of Neurosurgery, the First Affiliated Hospital, Harbin Medical University, Harbin, China.
Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, Florida, USA.
Int J Cancer. 2017 Oct 1;141(7):1434-1444. doi: 10.1002/ijc.30830. Epub 2017 Jul 5.
Tumor migration/metastasis and immunosuppression are major obstacles in effective cancer therapy. Incidentally, these 2 hurdles usually coexist inside tumors, therefore making therapy significantly more complicated, as both oncogenic mechanisms must be addressed for successful therapeutic intervention. Our recent report highlights that the tumor expression of a TNF family member, CD70, is correlated with poor survival for primary gliomas. In this study, we investigated how CD70 expression by GBM affects the characteristics of tumor cells and the tumor microenvironment. We found that the ablation of CD70 in primary GBM decreased CD44 and SOX2 gene expression, and inhibited tumor migration, growth and the ability to attract monocyte-derived M2 macrophages in vitro. In the tumor microenvironment, CD70 was associated with immune cell infiltrates, such as T cells; myeloid-derived suppressor cells; and monocytes/macrophages based on the RNA-sequencing profile. The CD163+ macrophages were far more abundant than T cells were. This overwhelming level of macrophages was identified only in GBM and not in low-grade gliomas and normal brain specimens, implying their tumor association. CD70 was detected only on tumor cells, not on macrophages, and was highly correlated with CD163 gene expression in primary GBM. Additionally, the co-expression of the CD70 and CD163 genes was found to correlate with decreased survival for patients with primary GBM. Together, these data suggest that CD70 expression is involved in promoting tumor aggressiveness and immunosuppression via tumor-associated macrophage recruitment/activation. Our current efforts to target this molecule using chimeric antigen receptor T cells hold great potential for treating patients with GBM.
肿瘤迁移/转移和免疫抑制是癌症有效治疗的主要障碍。碰巧的是，这两个障碍通常同时存在于肿瘤内部，因此使治疗变得更加复杂，因为为了成功的治疗干预，必须解决致癌机制。我们最近的报告强调，肿瘤表达 TNF 家族成员 CD70 与原发性神经胶质瘤的不良预后相关。在这项研究中，我们研究了 GBM 中 CD70 的表达如何影响肿瘤细胞和肿瘤微环境的特征。我们发现，原发性 GBM 中 CD70 的缺失降低了 CD44 和 SOX2 基因的表达，并抑制了肿瘤的迁移、生长以及体外吸引单核细胞衍生的 M2 巨噬细胞的能力。在肿瘤微环境中，根据 RNA 测序图谱，CD70 与免疫细胞浸润有关，如 T 细胞、髓系来源的抑制细胞和单核细胞/巨噬细胞。CD163+巨噬细胞比 T 细胞丰富得多。这种巨噬细胞的压倒性水平仅在 GBM 中被识别，而不在低级别神经胶质瘤和正常脑组织标本中被识别，表明它们与肿瘤有关。CD70 仅在肿瘤细胞上检测到，而不在巨噬细胞上检测到，并且与原发性 GBM 中 CD163 基因的表达高度相关。此外，发现 CD70 和 CD163 基因的共表达与原发性 GBM 患者的生存率降低相关。总之，这些数据表明，CD70 的表达通过肿瘤相关巨噬细胞的募集/激活参与促进肿瘤侵袭性和免疫抑制。我们目前使用嵌合抗原受体 T 细胞靶向该分子的努力为治疗 GBM 患者提供了巨大的潜力。
