Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611.
Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611
Proc Natl Acad Sci U S A. 2019 Nov 19;116(47):23714-23723. doi: 10.1073/pnas.1906346116. Epub 2019 Nov 11.
Tumor-associated myeloid cells (TAMCs) are key drivers of immunosuppression in the tumor microenvironment, which profoundly impedes the clinical response to immune-dependent and conventional therapeutic modalities. As a hallmark of glioblastoma (GBM), TAMCs are massively recruited to reach up to 50% of the brain tumor mass. Therefore, they have recently been recognized as an appealing therapeutic target to blunt immunosuppression in GBM with the hope of maximizing the clinical outcome of antitumor therapies. Here we report a nano-immunotherapy approach capable of actively targeting TAMCs in vivo. As we found that programmed death-ligand 1 (PD-L1) is highly expressed on glioma-associated TAMCs, we rationally designed a lipid nanoparticle (LNP) formulation surface-functionalized with an anti-PD-L1 therapeutic antibody (αPD-L1). We demonstrated that this system (αPD-L1-LNP) enabled effective and specific delivery of therapeutic payload to TAMCs. Specifically, encapsulation of dinaciclib, a cyclin-dependent kinase inhibitor, into PD-L1-targeted LNPs led to a robust depletion of TAMCs and an attenuation of their immunosuppressive functions. Importantly, the delivery efficiency of PD-L1-targeted LNPs was robustly enhanced in the context of radiation therapy (RT) owing to the RT-induced up-regulation of PD-L1 on glioma-infiltrating TAMCs. Accordingly, RT combined with our nano-immunotherapy led to dramatically extended survival of mice in 2 syngeneic glioma models, GL261 and CT2A. The high targeting efficiency of αPD-L1-LNP to human TAMCs from GBM patients further validated the clinical relevance. Thus, this study establishes a therapeutic approach with immense potential to improve the clinical response in the treatment of GBM and warrants a rapid translation into clinical practice.
肿瘤相关髓系细胞（TAMCs）是肿瘤微环境中免疫抑制的关键驱动因素，这极大地阻碍了对免疫依赖性和常规治疗方式的临床反应。作为胶质母细胞瘤（GBM）的一个标志，TAMCs 大量募集，达到脑肿瘤肿块的 50%。因此，它们最近被认为是一种有吸引力的治疗靶点，以削弱 GBM 中的免疫抑制，希望最大限度地提高抗肿瘤治疗的临床效果。在这里，我们报告了一种能够在体内主动靶向 TAMCs 的纳米免疫治疗方法。由于我们发现程序性死亡配体 1（PD-L1）在胶质瘤相关 TAMCs 上高度表达，我们合理设计了一种表面功能化有抗 PD-L1 治疗性抗体（αPD-L1）的脂质纳米颗粒（LNP）制剂。我们证明，该系统（αPD-L1-LNP）能够有效地将治疗有效载荷特异性递送至 TAMCs。具体而言，将周期蛋白依赖性激酶抑制剂地西他滨包封到 PD-L1 靶向的 LNPs 中，导致 TAMCs 的大量耗竭，并减弱其免疫抑制功能。重要的是，由于 RT 诱导胶质瘤浸润性 TAMCs 上 PD-L1 的上调，PD-L1 靶向 LNP 的递送效率在放射治疗（RT）的情况下得到了显著增强。相应地，RT 联合我们的纳米免疫治疗导致 2 种同源性胶质母细胞瘤模型（GL261 和 CT2A）中小鼠的存活时间显著延长。αPD-L1-LNP 对来自 GBM 患者的人 TAMCs 的高靶向效率进一步验证了其临床相关性。因此，这项研究建立了一种具有巨大潜力的治疗方法，可以改善 GBM 的临床反应，并需要迅速转化为临床实践。
