肿瘤细胞治疗研究
英文原题：Non-pathogenic E. coli displaying decoy-resistant IL18 mutein boosts anti-tumor and CAR NK cell responses.
肿瘤微环境可通过免疫细胞迁移不良和耗竭等机制抑制癌症疗法的疗效。
肿瘤微环境可通过免疫细胞迁移能力差和耗竭等机制抑制癌症治疗效果。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、肿瘤趋向性和易于基因操作等特点，通过在 E. coli K-12 DH5α 外膜表面展示关键免疫激活细胞因子，将其递送至肿瘤。表达小鼠诱饵抗性 IL18 突变体（DR18）的非致病性 E. coli，在免疫功能完整的结直肠癌和黑色素瘤小鼠模型中诱导强效、依赖 CD8+ T 细胞和自然杀伤（NK）细胞的免疫应答，并抑制肿瘤进展。经工程化改造、表面展示人 DR18 的 E. coli K-12 DH5α 能强效激活靶向间皮素的嵌合抗原受体（CAR）NK 细胞，并增强其向肿瘤迁移；在对 NK 细胞治疗耐药的间皮瘤异种移植模型中，该菌通过增强 TNF 信号并上调 NK 细胞激活标志物延长了生存期。我们的活菌免疫治疗系统可在治疗耐药实体瘤中安全、有效地诱导强效抗肿瘤应答，支持在临床进一步评估这一方法。
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 DH5 . 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 DH5 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.
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