Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
JCI Insight. 2019 Jul 11;4(13). doi: 10.1172/jci.insight.128217.
Oncolytic viruses induce local tumor destruction and inflammation. Whether virotherapy can also overcome immunosuppression in noninfected tumor areas is under debate. To address this question, we have explored immunologic effects of oncolytic herpes simplex viruses (oHSVs) in a genetically engineered mouse model of isocitrate dehydrogenase (IDH) wild-type glioblastoma, the most common and most malignant primary brain tumor in adults. Our model recapitulates the genomics, the diffuse infiltrative growth pattern, and the extensive macrophage-dominant immunosuppression of human glioblastoma. Infection with an oHSV that was armed with a UL16-binding protein 3 (ULBP3) expression cassette inhibited distant tumor growth in the absence of viral spreading (abscopal effect) and yielded accumulation of activated macrophages and T cells. There was also abscopal synergism of oHSVULBP3 with anti-programmed cell death 1 (anti-PD-1) against distant, uninfected tumor areas; albeit consistent with clinical trials in patients with glioblastoma, monotherapy with anti-PD-1 was ineffective in our model. Arming oHSV with ULBP3 led to upregulation of antigen processing and presentation gene sets in myeloid cells. The cognate ULBP3 receptor NKG2D, however, is not present on myeloid cells, suggesting a noncanonical mechanism of action of ULBP3. Overall, the myeloid-dominant, anti-PD-1-sensitive abscopal effect of oHSVULBP3 warrants further investigation in patients with IDH wild-type glioblastoma.
溶瘤病毒可诱导局部肿瘤破坏和炎症。溶瘤病毒是否也能克服未感染肿瘤区域的免疫抑制仍存在争议。为了回答这个问题，我们在异柠檬酸脱氢酶（IDH）野生型胶质母细胞瘤的基因工程小鼠模型中探索了溶瘤单纯疱疹病毒（oHSV）的免疫效应，IDH 野生型胶质母细胞瘤是成人中最常见和最恶性的原发性脑肿瘤。我们的模型重现了人类胶质母细胞瘤的基因组、弥漫浸润性生长模式和广泛的巨噬细胞主导的免疫抑制。携带 UL16 结合蛋白 3（ULBP3）表达盒的 oHSV 感染可在没有病毒扩散的情况下抑制远处肿瘤的生长（远隔效应），并导致激活的巨噬细胞和 T 细胞的积累。oHSVULBP3 与抗程序性细胞死亡 1（抗 PD-1）联合应用对远处未感染的肿瘤区域也有远隔协同作用；尽管与胶质母细胞瘤患者的临床试验一致，但我们的模型中单用抗 PD-1 是无效的。用 ULBP3 武装 oHSV 可导致髓样细胞中抗原加工和呈递基因集的上调。然而，相应的 ULBP3 受体 NKG2D 不存在于髓样细胞上，这表明 ULBP3 可能存在非典型作用机制。总之，oHSVULBP3 引起的以髓样细胞为主、抗 PD-1 敏感的远隔效应值得进一步在 IDH 野生型胶质母细胞瘤患者中进行研究。
