Department of Chemistry, The University of Chicago, Chicago, IL, 60637, USA.
Department of Radiology, The University of Chicago, Chicago, IL, 60637, USA.
Nat Commun. 2018 Jun 15;9(1):2351. doi: 10.1038/s41467-018-04703-w.
Checkpoint blockade immunotherapy enhances systemic antitumor immune response by targeting T cell inhibitory pathways; however, inadequate T cell infiltration has limited its anticancer efficacy. Radiotherapy (RT) has local immunomodulatory effects that can alter the microenvironment of irradiated tumors to synergize with immune checkpoint blockade. However, even with high doses of radiation, RT has rarely elicited systemic immune responses. Herein, we report the design of two porous Hf-based nanoscale metal-organic frameworks (nMOFs) as highly effective radioenhancers that significantly outperform HfO, a clinically investigated radioenhancer in vitro and in vivo. Importantly, the combination of nMOF-mediated low-dose RT with an anti-programmed death-ligand 1 antibody effectively extends the local therapeutic effects of RT to distant tumors via abscopal effects. Our work establishes the feasibility of combining nMOF-mediated RT with immune checkpoint blockade to elicit systemic antitumor immunity in non-T cell-inflamed tumor phenotypes without normal tissue toxicity, promising to broaden the application of checkpoint blockade immunotherapy.
检查点阻断免疫疗法通过靶向 T 细胞抑制途径增强全身抗肿瘤免疫反应；然而，不足的 T 细胞浸润限制了其抗癌疗效。放射治疗 (RT) 具有局部免疫调节作用，可以改变照射肿瘤的微环境，与免疫检查点阻断协同作用。然而，即使采用高剂量的辐射，RT 也很少引起全身免疫反应。在此，我们报告了两种多孔 Hf 基纳米级金属有机骨架 (nMOF) 的设计，作为高效的放射增敏剂，在体外和体内均显著优于临床研究的 HfO 放射增敏剂。重要的是，nMOF 介导的低剂量 RT 与抗程序性死亡配体 1 抗体的联合使用，通过远隔效应有效地将 RT 的局部治疗效果扩展到远处肿瘤。我们的工作确立了将 nMOF 介导的 RT 与免疫检查点阻断相结合，在非 T 细胞浸润的肿瘤表型中引发全身抗肿瘤免疫的可行性，而不会产生正常组织毒性，有望拓宽免疫检查点阻断免疫疗法的应用。
