Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA.
Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Centre, Los Angeles, CA, USA.
Nat Commun. 2021 Oct 8;12(1):5908. doi: 10.1038/s41467-021-26003-6.
Oncolytic herpes simplex virus-1 is capable of lysing tumor cells while alerting the immune system. CD47, in collaboration with SIRPα, represents an important immune checkpoint to inhibit phagocytosis by innate immune cells. Here we show locoregional control of glioblastoma by an oncolytic herpes virus expressing a full-length anti(α)-human CD47 IgG1 or IgG4 antibody. The antibodies secreted by the virus-infected glioblastoma cells block the CD47 'don't eat me' signal irrespective of the subclass; however, αCD47-IgG1 has a stronger tumor killing effect than αCD47-IgG4 due to additional antibody-dependent cellular phagocytosis by macrophages and antibody-dependent cellular cytotoxicity by NK cells. Intracranially injected αCD47-IgG1-producing virus continuously releases the respective antibody in the tumor microenvironment but not into systemic circulation; additionally, αCD47-IgG1-producing virus also improves the survival of tumor-bearing mice better than control oncolytic herpes virus combined with topical αCD47-IgG1. Results from immunocompetent mouse tumor models further confirm that macrophages, and to a lesser extent NK cells, mediate the anti-tumor cytotoxicity of antibody-producing oncolytic herpesviruses. Collectively, oncolytic herpes simplex virus-1 encoding full-length antibodies could improve immune-virotherapy for glioblastoma.
溶瘤单纯疱疹病毒 1 能够裂解肿瘤细胞，同时提醒免疫系统。CD47 与 SIRPα 合作，代表了一种重要的免疫检查点，以抑制先天免疫细胞的吞噬作用。在这里，我们展示了表达全长抗（α）-人 CD47 IgG1 或 IgG4 抗体的溶瘤单纯疱疹病毒对胶质母细胞瘤的局部控制。病毒感染的胶质母细胞瘤细胞分泌的抗体阻断了 CD47 的“不要吃我”信号，无论抗体的亚类如何；然而，由于巨噬细胞的抗体依赖细胞吞噬作用和 NK 细胞的抗体依赖细胞细胞毒性，αCD47-IgG1 比αCD47-IgG4 具有更强的肿瘤杀伤作用。颅内注射产生αCD47-IgG1 的病毒会在肿瘤微环境中持续释放相应的抗体，但不会进入体循环；此外，与联合使用局部αCD47-IgG1 的对照溶瘤单纯疱疹病毒相比，产生αCD47-IgG1 的病毒也能更好地提高荷瘤小鼠的存活率。免疫功能正常的小鼠肿瘤模型的结果进一步证实，巨噬细胞，以及在较小程度上的 NK 细胞，介导产生抗体的溶瘤单纯疱疹病毒的抗肿瘤细胞毒性。总之，编码全长抗体的溶瘤单纯疱疹病毒 1 可以改善胶质母细胞瘤的免疫病毒疗法。
