# Microbes as Medicines: Harnessing the Power of Bacteria in Advancing Cancer Treatment
## 2 Mechanism of Tumor Suppression
### Bacteria Tumor Immunotherapy  
The immune system plays a critical role in tumor immunosurveillance. Abnormal cells are recognized and eliminated with the help of innate and adaptive immunity in a continuous and bidirectional manner [93]. Tumor evolution occurs in three phases of \"immunoediting\" namely--elimination, equilibrium, and escape phase. NK cells and cytotoxic T-Lymphocytes (CD8+) are the primary mediators in the process along with other mediators including macrophages associated to tumors, dendritic cells, naive T cells, and regulatory T cells (T-regs). The microbial products and pathogen-associated molecular patterns lead to the activation of immune response [94]. Innate immunity is provided by the NK cells and these cells can recognize and eliminate the neoplastic cells. Once activated, NK cells accompanied by CD8+ T cells induce the recruitment and proliferation of other cells at the tumor site. This is attained by the release of cytokines such as interferon-gamma (IFN-\(\gamma\)), TNF, granulocyte and macrophage colony stimulating factor [1,93]. Cytokines induce apoptosis in tumor cells by anti-angiogenic effect on the tumor vasculature. For example, _Salmonella typhimurium_ expressing and secreting recombinant IFN-\(\gamma\) demonstrated enhanced tumoricidal effect and prolonged the survival of melanoma tumor bearing syngeneic mouse model. The IFN-\(\gamma\) directly activated the NK cell and the macrophages leading to more effective tumor suppression [95]. Commercially available bioproduct of _Staphylococcus aureus_ metabolites (consisting of enterotoxins, proteins, and amino acids) was found to be effective in the treatment of mesothelioma in orthotopic mouse models. The efficacy was attributed to the local activation of T-lymphocytes with significant activation of CD4+ and CD8+ T-cells leading to tumor necrosis [96]. Hydrodynamic tail vein injection of IL-21 in combination with attenuated _Salmonella typhimurium_ (VNP20009), exhibited suppression of tumor growth and prolonged mice survival in a melanoma model. The smaller tumor size and longer survival time was observed in combination therapy than when administered alone. The anti-tumor immune response was attributed to the higher concentration of CD4+ and CD8+ lymphocytes and NK cells infiltration at the tumor site [97].  
Bacteria also secrete certain immunomodulatory agents that are effective against cancer. Gram-negative bacteria produce outer membrane vesicles which induce anti-tumor responses by preferentially accumulating at the tumor site and stimulate the release of anti-tumor cytokines CXCL10 and IFN-\(\gamma\)[98]. To decipher the immune response pathways in bacteriolytic therapy employing _Clostridium novyi_--NT spores, immune cell function was analyzed in dogs developing neoplasia naturally. The study was aimed at studying the difference in immune response when the _Clostridial_ spores were administered via the intravenous and intratumoral route. The intratumoral injection enhanced phagocytosis and NK cell like function however, intravenous injection exhibited increased lipopolysaccharideacharide induced TNF\(\alpha\) and lipoteichoic acid induced IL-10 production. A sustained increase in phagocytic and NK cell function indicated long term immune cell function changes which can possibly have association with tumor remission [99]. _Enterococcus hirae_ and _Barnesiella intestinalinominis_ enhanced the immunomodulatory effects of cyclophosphamide by elevated CD8/T-reg ratio and promotion of interferon infiltration, respectively. The Th1 cell immune responses induced by these bacterial strains is predicted to have longer progression free survival in ovarian and lung cancer patients subjected to chemo-immunotherapy [100].