Engineered Bacteria Enhance Immunotherapy and Targeted Therapy through Stromal Remodeling of Tumors.
Engineered Bacteria Enhance Immunotherapy and Targeted Therapy through Stromal Remodeling of Tumors.
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DOI：
10.1002/adhm.202101487
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发表时间：
2022-01
影响因子：
10
通讯作者：
Kotagiri N
中科院分区：
文献类型：
--
作者：
Thomas SC;Madaan T;Kamble NS;Siddiqui NA;Pauletti GM;Kotagiri N
促纤维增生性实体瘤的特征是细胞外基质大分子（例如透明质酸（HA））的快速积聚。由此产生的生理屏障可防止免疫细胞的渗透，并阻碍抗癌药物的输送。我们报告了基于过度泡化大肠杆菌尼氏 (ΔECHy) 的肿瘤靶向细菌系统的开发，该系统能够通过外膜囊泡 (OMV) 分配融合肽溶细胞素 A (ClyA)-透明质酸酶 (Hy)。靶向缺氧肿瘤、原位制造重组蛋白的能力以及基于 OMV 的现场分配系统的额外优势使工程细菌载体成为肽递送的独特候选者。 Hy 对基质调节的 HA 降解潜力与 ClyA 的细胞溶解活性相结合，然后在同基因癌症模型中对其进行测试。 ΔECHy 与免疫检查点抗体和酪氨酸激酶抑制剂相结合，证明肿瘤基质重塑可以改善免疫治疗结果并增强生物信号抑制剂的功效。 ΔECHy 的生物相容性也经过研究，表明工程细菌被有效清除，引起最小的炎症和免疫反应，因此可能成为活生物治疗的可靠候选者。能够定位于肿瘤的工程化过度囊泡大肠杆菌 Nissle 可通过外膜囊泡递送溶细胞素 A (ClyA)-透明质酸酶 (Hy) 融合蛋白，以调节肿瘤基质。重组 Hy 减少肿瘤组织透明质酸，从而提高抗癌药物的渗透性，并增强其在乳腺癌和结肠癌小鼠模型中的作用。
Desmoplastic solid tumors are characterized by the rapid build-up of extracellular matrix macromolecules, such as Hyaluronic acid (HA). The resulting physiological barrier prevents the infiltration of immune cells and also impedes the delivery of anticancer agents. We report the development of a hypervesiculating E.coli Nissle (ΔECHy) based tumor targeting bacterial system capable of distributing a fusion peptide, Cytolysin A (ClyA)-Hyaluronidase (Hy) via outer membrane vesicles (OMVs). The capability of targeting hypoxic tumors, manufacturing recombinant proteins in-situ and the added advantage of an on-site OMV based distribution system makes the engineered bacterial vector a unique candidate for peptide delivery. The HA degrading potential of Hy for stromal modulation is combined with the cytolytic activity of ClyA followed by testing it within syngeneic cancer models. ΔECHy is combined with immune checkpoint antibodies and tyrosine kinase inhibitors to demonstrate that remodeling the tumor stroma results in the improvement of immunotherapy outcomes and enhancing the efficacy of biological signaling inhibitors. The biocompatibility of ΔECHy is also investigated to show that the engineered bacteria is effectively cleared, elicits minimal inflammatory and immune responses, and therefore could be a reliable candidate as a live biotherapeutic. Engineered hypervesiculating E.coli Nissle capable of localizing in tumors is utilized to deliver the Cytolysin A (ClyA)-Hyaluronidase (Hy) fusion protein by outer membrane vesicles to modulate the tumor matrix. Recombinant Hy decreases tumor tissue hyaluronic acid thereby improving the penetrability of anticancer agents and potentiation their effect in mouse models of breast and colon cancer.
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影响因子：
3.7
作者：
Crowe A;Zheng W;Miller J;Pahwa S;Alam K;Fung KM;Rubin E;Yin F;Ding K;Yue W
通讯作者：
Yue W
DOI：
10.1016/j.pbiomolbio.2019.03.005
发表时间：
2019-10
影响因子：
3.8
作者：
Caldwell BJ;Bell CE
通讯作者：
Bell CE
影响因子：
5.7
作者：
Ebelt, Nancy D.;Zuniga, Edith;Manuel, Edwin R.
通讯作者：
Manuel, Edwin R.
DOI：
10.1073/pnas.86.7.2172
发表时间：
1989-04-01
影响因子：
11.1
作者：
CHUNG, CT;NIEMELA, SL;MILLER, RH
通讯作者：
MILLER, RH
影响因子：
12.4
作者：
Jiang, Sheng-Nan;Phan, Thuy X.;Min, Jung-Joon
通讯作者：
Min, Jung-Joon