关键词： AKT, Akt serine/threonine kinase Bacteria-mediated cancer therapy CFU, colony-forming units CTLA-4, cytotoxic T-lymphocyte-associated protein 4 Cancer immune therapy DN, dominant-negative ERBB2, Erb-B2 receptor tyrosine kinase 2 ERKl, extracellular regulated protein kinase 1 Flagellin Flagellum GAPDH, glyceraldehyde-3-phosphate dehydrogenase GFP, green fluorescent protein IFN-γ, interferon-γ IL, interleukins IκB, inhibitor of NF-κB JNK, c-Jun N-terminal kinase LPS, lipopolysaccharide LRR, leucine-rich repeat MyD88, myeloid differentiation factor 88 NF-κB NF-κB, nuclear factor kappa-B PBS, phosphate-buffered saline PCR, polymerase chain reaction PD-1, programmed cell death protein-1 PD-L1, programmed cell death-ligand 1 PEI, polyethylenimine Salmonella TIR, Toll/Interleukin-1 receptor TLR, Toll-like receptor TLR5 TME, tumor microenvironment TRAF6, TNF receptor associated factor 6 VNP20009 i.p., intraperitoneally i.t., intratumorally

来  源：   DOI：10.1016/j.apsb.2021.04.019   PDF(Sci-hub)   PDF(Pubmed)

Abstract：
mediated cancer therapy has achieved remarkable anti-tumor effects in experimental animal models, but the detailed mechanism remains unsolved. In this report, the active involvement of the host immune response in this process was confirmed by comparing the tumor-suppressive effects of Salmonella in immunocompetent and immunodeficient mice bearing melanoma allografts. Since flagella are key inducers of the host immune response during bacterial infection, flagella were genetically disrupted to analyse their involvement in Salmonella-mediated cancer therapy. The results showed that flagellum-deficient strains failed to induce significant anti-tumor effects, even when more bacteria were administered to offset the difference in invasion efficiency. Flagella mainly activate immune cells via Flagellin/Toll-like receptor 5 (TLR5) signalling pathway. Indeed, we showed that exogenous activation of TLR5 signalling by recombinant Flagellin and exogenous expression of TLR5 both enhanced the therapeutic efficacy of flagellum-deficient Salmonella against melanoma. Our study highlighted the therapeutic value of the interaction between Salmonella and the host immune response through Flagellin/TLR5 signalling pathway during Salmonella-mediated cancer therapy, thereby suggesting the potential application of TLR5 agonists in the cancer immune therapy.
摘要：
介导的肿瘤治疗在实验动物模型中取得了显著的抗肿瘤效果,但是详细的机制仍未解决。在这份报告中,通过比较沙门氏菌在携带黑色素瘤同种异体移植物的免疫活性和免疫缺陷小鼠中的肿瘤抑制作用，证实了宿主免疫反应在这一过程中的积极参与。由于鞭毛是细菌感染过程中宿主免疫反应的关键诱导剂，鞭毛被基因破坏，以分析它们在沙门氏菌介导的癌症治疗中的参与。结果表明，鞭毛缺失菌株未能诱导显著的抗肿瘤作用，即使使用更多的细菌来抵消入侵效率的差异。鞭毛主要通过鞭毛蛋白/Toll样受体5(TLR5)信号通路激活免疫细胞。的确,我们发现通过重组鞭毛蛋白对TLR5信号的外源性激活和TLR5的外源性表达均增强了鞭毛缺陷型沙门氏菌对黑色素瘤的治疗功效。我们的研究强调了沙门氏菌介导的癌症治疗过程中通过鞭毛蛋白/TLR5信号通路与宿主免疫反应相互作用的治疗价值。从而提示TLR5激动剂在肿瘤免疫治疗中的潜在应用。
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