Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas, USA.
Department of Pediatric Hematology & Oncology, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.
Neuro Oncol. 2024 Sep 5;26(9):1602-1616. doi: 10.1093/neuonc/noae105.
The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy underscores its therapeutic promise and safety as a cancer immunotherapy. Despite this promise, the current efficacy of oHSV is significantly limited to a small subset of patients largely due to the resistance in tumor and tumor microenvironment (TME).
RNA sequencing (RNA-Seq) was used to identify molecular targets of oHSV resistance. Intracranial human and murine glioma or breast cancer brain metastasis (BCBM) tumor-bearing mouse models were employed to elucidate the mechanism underlying oHSV therapy-induced resistance.
Transcriptome analysis identified IGF2 as one of the top-secreted proteins following oHSV treatment. Moreover, IGF2 expression was significantly upregulated in 10 out of 14 recurrent GBM patients after treatment with oHSV, rQNestin34.5v.2 (71.4%; P = .0020) (ClinicalTrials.gov, NCT03152318). Depletion of IGF2 substantially enhanced oHSV-mediated tumor cell killing in vitro and improved survival of mice bearing BCBM tumors in vivo. To mitigate the oHSV-induced IGF2 in the TME, we constructed a novel oHSV, oHSV-D11mt, secreting a modified IGF2R domain 11 (IGF2RD11mt) that acts as IGF2 decoy receptor. Selective blocking of IGF2 by IGF2RD11mt significantly increased cytotoxicity, reduced oHSV-induced neutrophils/PMN-MDSCs infiltration, and reduced secretion of immune suppressive/proangiogenic cytokines, while increased CD8 + cytotoxic T lymphocytes (CTLs) infiltration, leading to enhanced survival in GBM or BCBM tumor-bearing mice.
This is the first study reporting that oHSV-induced secreted IGF2 exerts a critical role in resistance to oHSV therapy, which can be overcome by oHSV-D11mt as a promising therapeutic advance for enhanced viro-immunotherapy.
FDA 批准溶瘤单纯疱疹病毒（oHSV）治疗方法，突显了其作为癌症免疫疗法的治疗潜力和安全性。尽管有这样的前景，但 oHSV 的当前疗效在很大程度上仅限于一小部分患者，主要是由于肿瘤和肿瘤微环境（TME）中的耐药性。
使用 RNA 测序（RNA-Seq）来鉴定 oHSV 耐药的分子靶标。颅内人源和鼠源神经胶质瘤或乳腺癌脑转移（BCBM）荷瘤小鼠模型被用于阐明 oHSV 治疗诱导的耐药性的机制。
转录组分析鉴定出 IGF2 是 oHSV 治疗后分泌的最重要的蛋白质之一。此外，在接受 oHSV、rQNestin34.5v.2（71.4%；P=0.0020）治疗的 14 例复发性 GBM 患者中有 10 例患者的 IGF2 表达明显上调（ClinicalTrials.gov，NCT03152318）。IGF2 的耗竭在体外显著增强了 oHSV 介导的肿瘤细胞杀伤作用，并改善了携带 BCBM 肿瘤的小鼠的生存。为了减轻 TME 中 oHSV 诱导的 IGF2，我们构建了一种新型 oHSV，oHSV-D11mt，其分泌一种修饰的 IGF2R 结构域 11（IGF2RD11mt），作为 IGF2 诱饵受体。IGF2RD11mt 对 IGF2 的选择性阻断显著增加了细胞毒性，减少了 oHSV 诱导的中性粒细胞/PMN-MDSCs 浸润，并减少了免疫抑制/促血管生成细胞因子的分泌，同时增加了 CD8+细胞毒性 T 淋巴细胞（CTLs）的浸润，从而提高了 GBM 或 BCBM 荷瘤小鼠的生存率。
这是第一项报道 oHSV 诱导的分泌 IGF2 在抵抗 oHSV 治疗中发挥关键作用的研究，oHSV-D11mt 可以克服这种作用，这是增强病毒免疫治疗的一种有前途的治疗进展。
