Lin Zhongda, Meng Fanqiang, Ma Yumeng, Zhang Chi, Zhang Zhirang, Yang Zhaoxin, Li Yuan, Hou Linlin, Xu Yuzhong, Liang Xin, Zhang Xudong
Shenzhen Key Laboratory for Systems Medicine in Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-Sen University, Sun Yat-Sen University, Shenzhen, 518107, Guangdong, China.
Department of Clinical Laboratory, Shenzhen Baoan Hospital, The Second Affiliated Hospital of Shenzhen University, Shenzhen, 518101, China.
Bioact Mater. 2023 Sep 26;32:12-27. doi: 10.1016/j.bioactmat.2023.09.007. eCollection 2024 Feb.
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 . Herein, we engineered attenuated 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 . 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- 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.
免疫检查点阻断（ICB）疗法能有效恢复T细胞对癌症的反应。然而，肿瘤中免疫细胞浸润不足的患者从ICB疗法中获得的治疗益处有限。合成生物学推动了利用肿瘤靶向细菌合成治疗药物来调节免疫的替代策略。在此，我们用基因回路改造减毒的VNP20009，使其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），从而招募树突状细胞（DCs）并增强T细胞启动以引发抗肿瘤反应。细菌产生的GM-CSF刺激骨髓来源的树突状细胞（BMDCs）成熟，而IL-7促进脾脏分离的T细胞增殖并抑制细胞毒性T细胞凋亡。实际上，工程化的VNP20009更倾向于在肿瘤中定殖，并通过增强DCs和T细胞浸润来抑制肿瘤生长。此外，经工程化细菌治疗后，肿瘤毒性的颗粒酶B CD8 T细胞和干扰素γ CD8 T细胞群体显著增加。GM-CSF-IL-7-VNP20009与PD-1抗体联合使用可协同抑制肿瘤进展并使其停滞。
