非致病大肠杆菌表现出耐诱饵的IL18静扰素促进抗肿瘤和CAR NK细胞反应
Non-pathogenic E. coli displaying decoy-resistant IL18 mutein boosts anti-tumor and CAR NK cell responses
影响因子:41.70000
分区:生物学1区 Top / 生物工程与应用微生物1区
发表日期:2024 Oct 04
作者:
Shaobo Yang, Michal Sheffer, Isabel E Kaplan, Zongqi Wang, Mubin Tarannum, Khanhlinh Dinh, Yasmin Abdulhamid, Eden Bobilev, Roman Shapiro, Rebecca Porter, Robert Soiffer, Jerome Ritz, John Koreth, Yun Wei, Peiru Chen, Ke Zhang, Valeria Márquez-Pellegrin, Shanna Bonanno, Neel Joshi, Ming Guan, Mengdi Yang, Deng Li, Chiara Bellini, Fuguo Liu, Jianzhu Chen, Catherine J Wu, David Barbie, Jiahe Li, Rizwan Romee
摘要
肿瘤微环境可以通过诸如不良运输和免疫细胞耗尽等机制来抑制癌症疗法的功效。在这里，为了应对这一挑战，我们利用了非致病性大肠杆菌（大肠杆菌）的遗传操纵的安全性，肿瘤的湿气和易于性，通过表面在大肠杆菌K-12DH5α的外膜上显示出对肿瘤的关键免疫激活细胞因子。非致病性大肠杆菌表达鼠诱导的IL18静脉素（DR18）诱导健壮的CD8+ T和天然杀伤剂（NK）细胞依赖性免疫反应，并抑制了免疫功能的结直肠癌癌和黑色素瘤小鼠模型的肿瘤进展。大肠杆菌K-12DH5α设计为展示人类DR18的强度激活的靶向间皮蛋白靶向嵌合抗原受体（CAR）NK细胞，并增强其运输到肿瘤中，从而通过增强抗NK细胞治疗治疗的中皮瘤性瘤模型，通过增强TNF信号和上升的NK Activation NK Activation Markers在NK细胞治疗中的生存率。我们的实时细菌的免疫治疗系统安全有效地诱导了耐治疗的实体瘤中有效的抗肿瘤反应，从而激发了对诊所中这种方法的进一步评估。
Abstract
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.