Neutrophil depletion enhanced the Clostridium novyi-NT therapy in mouse and rabbit tumor models.
Neutrophil depletion enhanced the Clostridium novyi-NT therapy in mouse and rabbit tumor models.
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DOI：
10.1093/noajnl/vdab184
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发表时间：
2022-01
期刊：
影响因子：
--
通讯作者：
Bai RY
中科院分区：
文献类型：
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作者：
Staedtke V;Gray-Bethke T;Liu G;Liapi E;Riggins GJ;Bai RY
缺氧是实体肿瘤的一个显著特征，它可以作为溶瘤性厌氧菌如Clostridium novyi-NT （C. novyi-NT）的肥沃环境，在小鼠和患者中诱导肿瘤破坏。然而，两大障碍限制了其使用，即宿主炎症反应和正常肿瘤区域的不完全清除。在这项研究中，我们首先在免疫功能正常的小鼠中使用胶质母细胞瘤（GBM）细胞系皮下肿瘤模型来研究肿瘤缺氧的局部分布、C. novyi-NT萌发和扩散的动力学以及局部宿主的免疫反应。随后，我们将获得的知识应用于开发C. novyi-NT治疗兔原位脑肿瘤模型。我们发现颗粒状白细胞的局部积聚，主要是中性粒细胞，可以阻止细菌通过肿瘤的扩散，阻止肿瘤的完全溶解。通过抗ly6g抗体或羟基脲抑制骨髓来消耗中性粒细胞可显著改善肿瘤清除。然后，我们将这种方法应用于植入侵袭性颅内脑肿瘤的兔子，并在大多数动物中实现了长期存活，没有明显的毒性。这些结果表明，消耗中性粒细胞可以大大提高C. novyi-NT治疗脑肿瘤的安全性和有效性。
Hypoxia is a prominent feature of solid tumors and can function as fertile environment for oncolytic anaerobic bacteria such as Clostridium novyi-NT (C. novyi-NT) where it can induce tumor destruction in mice and patients. However, two major obstacles have limited its use, namely the host inflammatory response and the incomplete clearance of normoxic tumor areas. In this study, we first used a subcutaneous tumor model of a glioblastoma (GBM) cell line in immunocompetent mice to investigate the local distribution of tumor hypoxia, kinetics of C. novyi-NT germination and spread, and the local host immune response. We subsequently applied the acquired knowledge to develop a C. novyi-NT therapy in an orthotopic rabbit brain tumor model. We found that local accumulation of granular leukocytes, mainly neutrophils, could impede the spread of bacteria through the tumor and prevent complete oncolysis. Depletion of neutrophils via anti-Ly6G antibody or bone marrow suppression using hydroxyurea significantly improved tumor clearance. We then applied this approach to rabbits implanted with an aggressive intracranial brain tumor and achieved long-term survival in majority of the animals without apparent toxicity. These results indicated that depleting neutrophils can greatly enhance the safety and efficacy of C. novyi-NT cancer therapy for brain tumors.