胶质母细胞瘤的遗传驱动因素决定了肿瘤相关巨噬细胞/小胶质细胞的功能以及对 CSF1R 抑制的反应。
Glioblastoma genetic drivers dictate the function of tumor-associated macrophages/microglia and responses to CSF1R inhibition.
机构信息
Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Medical Scientist Training Program, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
出版信息
Neuro Oncol. 2022 Apr 1;24(4):584-597. doi: 10.1093/neuonc/noab228.
BACKGROUND
Tumor-associated macrophages/microglia (TAMs) are prominent microenvironment components in human glioblastoma (GBM) that are potential targets for anti-tumor therapy. However, TAM depletion by CSF1R inhibition showed mixed results in clinical trials. We hypothesized that GBM subtype-specific tumor microenvironment (TME) conveys distinct sensitivities to TAM targeting.
METHODS
We generated syngeneic PDGFB- and RAS-driven GBM models that resemble proneural-like and mesenchymal-like gliomas, and determined the effect of TAM targeting by CSF1R inhibitor PLX3397 on glioma growth. We also investigated the co-targeting of TAMs and angiogenesis on PLX3397-resistant RAS-driven GBM. Using single-cell transcriptomic profiling, we further explored differences in TME cellular compositions and functions in PDGFB- and RAS-driven gliomas.
RESULTS
We found that growth of PDGFB-driven tumors was markedly inhibited by PLX3397. In contrast, depletion of TAMs at the early phase accelerated RAS-driven tumor growth and had no effects on other proneural and mesenchymal GBM models. In addition, PLX3397-resistant RAS-driven tumors did not respond to PI3K signaling inhibition. Single-cell transcriptomic profiling revealed that PDGFB-driven gliomas induced expansion and activation of pro-tumor microglia, whereas TAMs in mesenchymal RAS-driven GBM were enriched in pro-inflammatory and angiogenic signaling. Co-targeting of TAMs and angiogenesis decreased cell proliferation and changed the morphology of RAS-driven gliomas.
CONCLUSIONS
Our work identifies functionally distinct TAM subpopulations in the growth of different glioma subtypes. Notably, we uncover a potential responsiveness of resistant mesenchymal-like gliomas to combined anti-angiogenic therapy and CSF1R inhibition. These data highlight the importance of characterization of the microenvironment landscape in order to optimally stratify patients for TAM-targeted therapy.
背景
肿瘤相关巨噬细胞/小胶质细胞（TAMs）是人类胶质母细胞瘤（GBM）中突出的微环境成分，是抗肿瘤治疗的潜在靶点。然而，CSF1R 抑制作用下的 TAM 耗竭在临床试验中结果不一。我们假设 GBM 亚型特异性肿瘤微环境（TME）对 TAM 靶向具有不同的敏感性。
方法
我们生成了 PDGFB 和 RAS 驱动的同源性 GBM 模型，这些模型类似于神经前体细胞样和间充质样神经胶质瘤，并确定了 CSF1R 抑制剂 PLX3397 对神经胶质瘤生长的 TAM 靶向作用的影响。我们还研究了 TAMs 与血管生成的共同靶向作用对 PLX3397 耐药的 RAS 驱动的 GBM 的影响。通过单细胞转录组谱分析，我们进一步探讨了 PDGFB 和 RAS 驱动的神经胶质瘤中 TME 细胞组成和功能的差异。
结果
我们发现 PLX3397 显著抑制了 PDGFB 驱动的肿瘤生长。相比之下，在早期阶段耗竭 TAMs 会加速 RAS 驱动的肿瘤生长，对其他神经前体细胞样和间充质样 GBM 模型没有影响。此外，PLX3397 耐药的 RAS 驱动的肿瘤对 PI3K 信号抑制无反应。单细胞转录组谱分析显示，PDGFB 驱动的神经胶质瘤诱导了促肿瘤小胶质细胞的扩张和激活，而间充质 RAS 驱动的 GBM 中的 TAMs 富含促炎和血管生成信号。TAMs 和血管生成的共同靶向作用降低了细胞增殖并改变了 RAS 驱动的神经胶质瘤的形态。
结论
我们的工作确定了不同神经胶质瘤亚型生长中具有不同功能的 TAM 亚群。值得注意的是，我们发现耐药间充质样神经胶质瘤对联合抗血管生成治疗和 CSF1R 抑制具有潜在的反应性。这些数据强调了对微环境特征进行特征描述的重要性，以便为 TAM 靶向治疗最佳分层患者。
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