Yang Shaobo, Sheffer Michal, Kaplan Isabel E, Wang Zongqi, Tarannum Mubin, Dinh Khanhlinh, Abdulhamid Yasmin, Bobilev Eden, Shapiro Roman, Porter Rebecca, Soiffer Robert, Ritz Jerome, Koreth John, Wei Yun, Chen Peiru, Zhang Ke, Márquez-Pellegrin Valeria, Bonanno Shanna, Joshi Neel, Guan Ming, Yang Mengdi, Li Deng, Bellini Chiara, Liu Fuguo, Chen Jianzhu, Wu Catherine J, Barbie David, Li Jiahe, Romee Rizwan
Department of Bioengineering, Northeastern University, Boston, MA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Nat Biotechnol. 2024 Oct 4. doi: 10.1038/s41587-024-02418-6.
The tumor microenvironment can inhibit the efficacy of cancer therapies through mechanisms such as poor trafficking and exhaustion of immune cells. Here, to address this challenge, we exploited the safety, tumor tropism and ease of genetic manipulation of non-pathogenic Escherichia coli (E. coli) to deliver key immune-activating cytokines to tumors via surface display on the outer membrane of E. coli K-12 DH5α. Non-pathogenic E. coli expressing murine decoy-resistant IL18 mutein (DR18) induced robust CD8 T and natural killer (NK) cell-dependent immune responses and suppressed tumor progression in immune-competent colorectal carcinoma and melanoma mouse models. E. coli K-12 DH5α engineered to display human DR18 potently activated mesothelin-targeting chimeric antigen receptor (CAR) NK cells and enhance their trafficking into tumors, which extended survival in an NK cell treatment-resistant mesothelioma xenograft model by enhancing TNF signaling and upregulating NK activation markers. Our live bacteria-based immunotherapeutic system safely and effectively induces potent anti-tumor responses in treatment-resistant solid tumors, motivating further evaluation of this approach in the clinic.
肿瘤微环境可通过免疫细胞运输不良和耗竭等机制抑制癌症治疗的疗效。在此，为应对这一挑战，我们利用非致病性大肠杆菌（E. coli）的安全性、肿瘤嗜性和易于基因操作的特点，通过在大肠杆菌K-12 DH5α外膜上进行表面展示，将关键的免疫激活细胞因子递送至肿瘤。表达抗诱饵小鼠IL18突变体（DR18）的非致病性大肠杆菌在免疫健全的结直肠癌和黑色素瘤小鼠模型中诱导了强大的CD8 T细胞和自然杀伤（NK）细胞依赖性免疫反应，并抑制了肿瘤进展。经过工程改造以展示人DR18的大肠杆菌K-12 DH5α有力地激活了靶向间皮素的嵌合抗原受体（CAR）NK细胞，并增强了它们向肿瘤的运输，通过增强TNF信号传导和上调NK激活标志物，延长了NK细胞治疗耐药的间皮瘤异种移植模型中的生存期。我们基于活细菌的免疫治疗系统在治疗耐药的实体瘤中安全有效地诱导了强大的抗肿瘤反应，促使在临床上对该方法进行进一步评估。
