Enhancing Immune Responses Toward Tumors By Bacterial Infections

The history of using bacteria in tumor therapy has a long record. Already more than 100 years ago, bacteria were employed by William Coley. Based on his observations on the coincidence of spontaneous tumor remissions and bacterial infections, he systematically treated cancer patients with viable infectious agents (Coley's toxin). By the application of different bacteria preparations, he could obtain impressive therapeutic effects including the complete regression of inoperable cancers in several patients (27,28). How can this acci-

Figure 1 Principles of bacteria-mediated gene transfer. (A) Plasmid DNA encoding the gene of choice is introduced into invasive bacteria such as Listeria or Shigella. After phagocytic uptake by the target cell, the recombinant bacteria escape from the phagosomal vacuole into the cytosol. The microbes die in the cytosol either due to metabolic auxotrophies, due to genetically engineered autolysins, or by antibiotic treatment. Thereby the plasmid is released, which subsequently obtains access to the nucleus of the infected cells for the foreign gene to be transcribed. The protein antigen is degraded by the proteasome and resulting peptides, containing the appropriate binding motif, are loaded onto MHC class I molecules in the ER (endoplasmatic reticulum). The peptide-MHC class I complex is then transported via the golgi to the cell surface. (B) Facultative intracellular bacteria of the species Salmonella are modified with plasmid DNA. The recombinant pathogens invade the host cell and establish themselves in the phagosome. The bacteria die (e.g., due to an auxotrophic attenuation) whereby the plasmid DNA can access the cytosol due to an unknown pathway. Subsequently, the plasmid is transferred to the nucleus of the cell where expression of the gene takes place.

Figure 1 Principles of bacteria-mediated gene transfer. (A) Plasmid DNA encoding the gene of choice is introduced into invasive bacteria such as Listeria or Shigella. After phagocytic uptake by the target cell, the recombinant bacteria escape from the phagosomal vacuole into the cytosol. The microbes die in the cytosol either due to metabolic auxotrophies, due to genetically engineered autolysins, or by antibiotic treatment. Thereby the plasmid is released, which subsequently obtains access to the nucleus of the infected cells for the foreign gene to be transcribed. The protein antigen is degraded by the proteasome and resulting peptides, containing the appropriate binding motif, are loaded onto MHC class I molecules in the ER (endoplasmatic reticulum). The peptide-MHC class I complex is then transported via the golgi to the cell surface. (B) Facultative intracellular bacteria of the species Salmonella are modified with plasmid DNA. The recombinant pathogens invade the host cell and establish themselves in the phagosome. The bacteria die (e.g., due to an auxotrophic attenuation) whereby the plasmid DNA can access the cytosol due to an unknown pathway. Subsequently, the plasmid is transferred to the nucleus of the cell where expression of the gene takes place.

dental finding of a connection between bacterial infections and tumor regressions be explained?

In principle, initiation of antigen-specific immunity is restricted to the lymphoid organs where the target antigens are presented to the T cells by mature dendritic cells. To do so, immature DCs pick up antigens in the periphery. Simultaneous to antigen uptake, DCs have to receive specific environmental signals that induce their activation and maturation. During this maturation process, they obtain migratory capacity toward secondary lymphoid organs and, in addition, become highly stimulatory for T cells by expression of costimulatory molecules. This, leads to antigen-specific T cell activation. With respect to this activation cascade, tumor cells lack the capacity to activate primary T cells, due to the absence of essential stimulatory functions. Although proteins derived from a tumor might be phagocytosed by immature dendritic cells, such DCs normally do not become activated and can therefore not function as inductors of a T cell response. Antigen presentation by immature DC is even considered to result in peripheral tolerance of T cells (Fig. 2). Thus, two opposite functions are attributed to antigen presenting DC depending on their maturation status: they may act as mediators of T cell tolerance or as central players in the induction of adaptive immune responses (29).

How can DC activation be induced? Inflammatory cyto-kines released in response to tissue damage during infection, as well as highly conserved molecular structures derived from the infectious agent itself, are mediators of DC activation. The latter substances can be considered conserved biochemical patterns that cannot be found in the mammalian host (e.g., unmethylated CpG motifs of bacterial DNA and lipids, such as lipopolysaccharide for Gram negative and lipoteichoic acid for Gram positive bacteria). These molecules bind to Tolllike receptors (TLRs) mainly expressed by cells of the innate immune system and induce their activation (30,31). Several other receptors, such as scavenger receptors, complement receptors, Fc receptors, and the like, might also be involved in the activation process (32). Stimulation via these receptors results in the production of inflammatory cytokines, which in turn might activate additional cell populations, including dendritic cells. Alternatively, DCs themselves can be activated directly by the recognition of pathogen structures through their own pattern recognition receptors. Activated DCs would be the link between the innate immune system and adaptive immunity starting with the activation of T cells of the Th1 type, which might provide essential help for the induction of pathogen-specific CTL (Fig. 2). Thus, the bacterial products are providing strong adjuvant activity that in the context of an antitumor response might be able to break tolerance toward tumor antigens or to circumvent escape mechanisms of the tumor.

One also could envision a scenario where DCs induce a specific immune response against pathogen-derived antigens, while initiating ''bystander activation'' of tumor-specific T cells. When large amounts of tumor antigens are taken up by DCs, this accidental coupling of T cell immunity against microbes and tumor appears to be possible (Fig. 2). This con cept might explain the therapeutic effects of Coley's toxin in cancer patients. Nevertheless, despite its effectiveness, this initial immunotherapeutic strategy was ignored for more then half a century, until in the 1960s, when the adjuvant effects of bacterial preparations were rediscovered by the successful use of BCG (Mycobacterium bovis strain Calmette-Guerin) in cancer therapy (33).

As a logical consequence, bacteria are now widely used as delivery system for various vaccination strategies, including immunizations against model tumors (34). This was recently extended to genetic vaccination (i.e., bacteria have been used as vehicles for transfer of eukaryotic expression plasmids encoding tumor antigens or immune stimulatory molecules). Obviously, the combination of the adjuvancy of a bacterial carrier and particular features of the antigen expression plasmid should synergize to induce protective antitumor responses. During bacteria-mediated DNA vaccination, DCs might acquire the tumor antigens from the bacterial carrier either by direct infection or via cross-presentation. In the latter case, the infected cell that contains the antigen is phagocytosed by neighboring DCs, which then are activated and represent the original antigens. Both routes, cross-priming and direct priming have been described for specific activation of T cells. In addition to genetic vaccination, bacterial carriers can also be used for gene therapy to improve the performance of the immune system or to directly target inhibitory molecules to the tumor cells.

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