In situ immunomodulation of tumors with biosynthetic bacteria promote anti-tumor immunity.
In situ immunomodulation of tumors with biosynthetic bacteria promote anti-tumor immunity.
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DOI：
10.1016/j.bioactmat.2023.09.007
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发表时间：
2024-02
影响因子：
18.9
通讯作者：
中科院分区：
文献类型：
--
作者：
免疫检查点阻断（ICB）疗法有效地恢复了T细胞对癌症的反应。然而，患有浸润免疫细胞不足的肿瘤的患者仅从ICB疗法获得有限的治疗益处。合成生物学促进了利用肿瘤靶向细菌合成治疗剂以原位调节免疫的替代策略。在此，我们用基因电路改造减毒鼠伤寒沙门氏菌VNP 20009，以在肿瘤内合成粒细胞-巨噬细胞集落刺激因子（GM-CSF）和白细胞介素7（IL-7），其募集树突状细胞（DC）并增强T细胞引发以引发抗肿瘤应答。细菌产生的GM-CSF刺激骨髓来源的树突状细胞（BMDCs）的成熟，而IL-7促进脾分离的T细胞的增殖并抑制细胞毒性T细胞的凋亡。事实上，工程VNP 20009更喜欢在肿瘤中定殖，并通过增强DC和T细胞浸润来抑制肿瘤生长。经工程菌处理后，GZMB+ CD 8 + T细胞和IFN-γ+ CD 8 + T细胞数量明显增加。GM-CSF-IL-7-VNP 20009与PD-1抗体的组合协同抑制肿瘤进展和停滞。构建了一株分泌诱导蛋白的工程沙门氏菌。细菌产生的GM-CSF和IL-7在体外具有生物学活性。在肿瘤内富集的工程沙门氏菌。工程沙门氏菌强烈抑制黑色素瘤的进展。
Immune checkpoint blockade (ICB) therapy potently revives T cell's response to cancer. However, patients suffered with tumors that had inadequate infiltrated immune cells only receive limited therapeutic benefits from ICB therapy. Synthetic biology promotes the alternative strategy of harnessing tumor-targeting bacteria to synthesize therapeutics to modulate immunity in situ. Herein, we engineered attenuated Salmonella typhimurium VNP20009 with gene circuits to synthetize granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 7 (IL-7) within tumors, which recruited dendritic cells (DCs) and enhanced T cell priming to elicit anti-tumor response. The bacteria-produced GM-CSF stimulated the maturation of bone marrow-derived dendritic cells (BMDCs), while IL-7 promoted the proliferation of spleen isolated T cells and inhibited cytotoxicity T cell apoptosis in vitro. Virtually, engineered VNP20009 prefer to colonize in tumors, and inhibited tumor growth by enhancing DCs and T cell infiltration. Moreover, the tumor-toxic GZMB+ CD8+ T cell and IFN-γ+ CD8+ T cell populations conspicuously increased with the treatment of engineered bacteria. The combination of GM–CSF–IL-7-VNP20009 with PD-1 antibody synergistically stunted the tumor progress and stasis. An inducible protein-secreting engineered Salmonella was constructed. Bacteria-produced GM-CSF and IL-7 had their biological activity in vitro. Engineered Salmonella enriched within tumors. Engineered Salmonella strongly inhibited the progression of melanoma.
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影响因子：
19
作者：
Chen, Qi-Wen;Liu, Xin-Hua;Zhang, Xian-Zheng
通讯作者：
Zhang, Xian-Zheng
影响因子：
6.4
作者：
Cattaruzza, Lara;Gloghini, Annunziata;Aldinucci, Donatella
通讯作者：
Aldinucci, Donatella
影响因子：
17.1
作者：
Gurbatri CR;Lia I;Vincent R;Coker C;Castro S;Treuting PM;Hinchliffe TE;Arpaia N;Danino T
通讯作者：
Danino T
影响因子：
16.6
作者：
通讯作者：
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DOI：
10.1073/pnas.2004421117
发表时间：
2020-08-04
影响因子：
11.1
作者：
Antonelli, Anthony C.;Binyamin, Anna;Redelman-Sidi, Gil
通讯作者：
Redelman-Sidi, Gil