• Identification of tumor-specific Salmonella Typhimurium promoters and their regulatory logic.

      Leschner, Sara; Deyneko, Igor V; Lienenklaus, Stefan; Wolf, Kathrin; Bloecker, Helmut; Bumann, Dirk; Loessner, Holger; Weiss, Siegfried; Molecular Immunology, Helmholtz Centre for Infection Research, Inhoffenstr. 7, 38124 Braunschweig, Germany. sara.leschner@helmholtz-hzi.de (2012-04)
      Conventional cancer therapies are often limited in effectiveness and exhibit strong side effects. Therefore, alternative therapeutic strategies are demanded. The employment of tumor-colonizing bacteria that exert anticancer effects is such a novel approach that attracts increasing attention. For instance, Salmonella enterica serovar Typhimurium has been used in many animal tumor models as well as in first clinical studies. These bacteria exhibit inherent tumoricidal effects. In addition, they can be used to deliver therapeutic agents. However, bacterial expression has to be restricted to the tumor to prevent toxic substances from harming healthy tissue. Therefore, we screened an S. Typhimurium promoter-trap library to identify promoters that exclusively drive gene expression in the cancerous tissue. Twelve elements could be detected that show reporter gene expression in tumors but not in spleen and liver. In addition, a DNA motif was identified that appears to be necessary for tumor specificity. Now, such tumor-specific promoters can be used to safely express therapeutic proteins by tumor-colonizing S. Typhimurium directly in the neoplasia.
    • Influence of infection route and virulence factors on colonization of solid tumors by Salmonella enterica serovar Typhimurium.

      Crull, Katja; Bumann, Dirk; Weiss, Siegfried; Dept. Molecular Immunology, Helmholtz Centre for infection research, Inhoffenstr. 7, D38124 Braunschweig, Germany. (2011-06)
      Administration of facultative anaerobic bacteria such as Salmonella enterica serovar Typhimurium as anticancer treatment holds a great therapeutic potential. Here, we tested different routes of application of S. typhimurium with regard to tumor colonization and therapeutic efficacy. No differences between intravenous and intraperitoneal infection were observed, often leading to a complete tumor clearance. In contrast, after oral application, tumor colonization was inefficient and delayed. No therapeutic effect was observed under such conditions. We also showed that tumor invasion and colonization were independent of functional Salmonella pathogenicity island (SPI) 1 and SPI 2. Furthermore, tumor invasion and colonization did not require bacterial motility or chemotactic responsiveness. The distribution of the bacteria within the tumor was independent of such functions.
    • Murine solid tumours as a novel model to study bacterial biofilm formation in vivo.

      Pawar, V; Crull, K; Komor, U; Kasnitz, N; Frahm, M; Kocijancic, D; Westphal, K; Leschner, S; Wolf, K; Loessner, H; et al. (2014-08)
      Bacteria of many species are able to invade and colonize solid tumours in mice. We have focused on Salmonella enterica serovar Typhimurium. Detailed analysis revealed that such tumour-invading Salmonella form biofilms, thus providing a versatile in vivo test system for studying bacterial phenotypes and host-pathogen interactions. It appears that biofilm formation by S. typhimurium is induced as a defence against the immune system of the host, and in particular against neutrophils. Further, we extended our work to the clinically more relevant biofilm infection by Pseudomonas aeruginosa. The induction of P. aeruginosa biofilms in neoplastic tissue appears to be elicited as a reaction against the immune system. Reconstitution experiments reveal that T cells are responsible for biofilm induction. Isogenic mutants that are no longer able to form biofilms can be used for comparison studies to determine antimicrobial resistance, especially therapeutic efficacy against P. aeruginosa located in biofilms.
    • Tumor invasion of Salmonella enterica serovar Typhimurium is accompanied by strong hemorrhage promoted by TNF-alpha.

      Leschner, Sara; Westphal, Kathrin; Dietrich, Nicole; Viegas, Nuno; Jablonska, Jadwiga; Lyszkiewicz, Marcin; Lienenklaus, Stefan; Falk, Werner; Gekara, Nelson; Loessner, Holger; et al. (2009)
      Several facultative anaerobic bacteria with potential therapeutic abilities are known to preferentially colonize solid tumors after systemic administration. How they efficiently find and invade the tumors is still unclear. However, this is an important issue to be clarified when bacteria should be tailored for application in cancer therapy.
    • Type I IFNs induce anti-tumor polarization of tumor associated neutrophils in mice and human.

      Andzinski, Lisa; Kasnitz, Nadine; Stahnke, Stephanie; Wu, Ching-Fang; Gereke, Marcus; von Köckritz-Blickwede, Maren; Schilling, Bastian; Brandau, Sven; Weiss, Siegfried; Jablonska, Jadwiga; et al. (2016-04-15)
      The importance of tumor associated neutrophils (TANs) in cancer development is in the meantime well established. Numerous of clinical data document the adverse prognostic effects of neutrophil infiltration in solid tumors. However, certain tumor therapies need functional neutrophils to be effective, suggesting altered neutrophil polarization associated with different outcomes for cancer patients. Therefore, modulation of neutrophilic phenotypes represents a potent therapeutic option, but factors mediating neutrophil polarization are still poorly defined. In this manuscript we provide evidence that type I IFNs alter neutrophilic phenotype into anti-tumor, both in mice and human. In the absence of IFN-β, pro-tumor properties, such as reduced tumor cytotoxicity with low neutrophil extracellular traps (NETs) expression, low ICAM1 and TNF-α expression, dominated neutrophil phenotypes in primary lesion and premetastatic lung. Interestingly, such neutrophils have significantly prolonged life-span. Notably, interferon therapy in mice altered TAN polarization towards anti-tumor N1. Similar changes in neutrophil activation could be observed in melanoma patients undergoing type I IFN therapy. Altogether, these data highlight the therapeutic potential of interferons, suggesting optimization of its clinical use as potent anti-tumor agent.