Salmonella flagella confer anti-tumor immunological effect via activating Flagellin/TLR5 signalling within tumor microenvironment

  • Acta Pharm Sin B. 2021 Oct;11(10):3165-3177. doi: 10.1016/j.apsb.2021.04.019.
Jianxiang Chen  1  2  3 ,  Yiting Qiao  1  4 ,  Guo Chen  1 ,  Cunjie Chang  2 ,  Heng Dong  2 ,  Bo Tang  5 ,  Xiawei Cheng  1 ,  Xiufeng Liu  1 ,  Zichun Hua  1  5  6
Affiliations
  • 1. School of Life Sciences, Nanjing University, Nanjing 210023, China.
  • 2. College of Pharmacy, School of Medicine, Hangzhou Normal University, Hangzhou 311100, China.
  • 3. Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou 311121, China.
  • 4. Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
  • 5. Changzhou High-Tech Research Institute of Nanjing University and Jiangsu TargetPharma Laboratories Inc., Changzhou 213164, China.
  • 6. School of Biopharmacy, China Pharmaceutical University, Nanjing 211198, China.
PMID: 34729307 DOI: 10.1016/j.apsb.2021.04.019
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.

Keywords
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.
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