# Bacterial Therapy of Cancer: A Way to the Dustbin of History or to the Medicine of the Future?
## 5 Bacteria in Cancer Therapy
### Mechanisms of Antitumor Action
#### 5.2.1 Stimulation of the Immune Response  
The immune system plays an important role in a tumor surveillance. Properly, abnormal cells are recognized and eliminated with the help of innate and adaptive immunity. The evolution of tumors occurs in some phases, namely in the elimination, equilibrium, and escape phases, when malicious cells become weakly immunogenic due to the development of tolerance and the immune system does not perceive them [90; 91; 92]. The immunotherapeutic strategy of cancer treatment supposes the stimulation of the immune system to destroy cancerous cells, and anticancer bacterial immunotherapeutic \"vaccines\", respectively, propose to employ bacteria to enhance the antigenicity of tumor cells. The key point in the induction of a systemic anticancer immune response is the ability of the immune system to recognize conserved pathogen-associated molecular patterns (PAMPs). Thus, the injection of any appropriate bacteria--killed or weakened--directlyinto the tumor has the potential to induce or restore the host immune response against the cancer. Moreover, the pioneer [PERSON], as well as some other researchers, tried applying not only intratumoral but also intravenous injections, resulting in durable cancer Emissions in both cases--although, in general, it seems that intratumoral injections are considered more effective [25; 93]. An even more rational way to increase the antigenicity of tumor cells is to try to create a vaccine based on isolated tumor-tropic microorganisms, as described in the previous sections. The question is, which part of the complex and multilevel immune system does the bacteria interfere with to stimulate it? There are several works on which bacteria can stimulate the host's immunity and target it in tumor cells, as well as the facts accumulated proving the involvement of a wide variety of immune-response mechanisms. As an example, consider one of the successful examples of the stimulation of the immune response by bacteria, the abovementioned BCG immunotherapy, which is considered as a gold-standard treatment for nonmuscle-invasive bladder cancer at a high risk of recurrence or progression. Preclinical and clinical studies have revealed that a robust inflammatory response to BCG consists of some steps, including: (1) the attachment of BCG; (2) the internalization of BCG into resident immune cells, normal cells, and tumor urothelial cells; (3) the BCG-mediated induction of innate immunity, which is orchestrated by a cellular and cytokine milieu; (4) the BCG-mediated initiation of tumor-specific immunity [74; 94]. Getting into the bladder, BCG interacts with the epithelium; there, the activation of epithelial cells and antigen-presenting cells that produce cytokines and chemokines is observed. The appearance of macrophages, dendritic cells, lymphocytes, and neutrophils is also observed in the bladder wall. In vitro studies with the use of human NIMBC (nonmuscle-invasive bladder cancer) cancer cell lines showed that BCG increases the production of IL-6 and IL-8, GM-CSF (granulocyte-macrophage colony-stimulating factor), and tumor necrosis factor (TNF). Furthermore, data obtained from studies on human subjects showed that, after the introduction of BCG, neutrophils, macrophages, monocytes, T and B lymphocytes, and NK cells were present in the bladder, accompanied by increased levels of IL-1, IL-8, IL-15, IL-18, CXCL10 (CXC motif chemokine ligand 10), CC motif chemokine ligand (CCL)2, CCL3, and GM-CSF [74; 95]. Neutrophils can directly affect tumor cells through their phagocytic activity and the ability to produce reactive oxygen species, the secretion of lytic enzymes, and factors inducing apoptosis, e.g., TRAIL (TNF-related apoptosis-inducing ligand). The role of NK cells in BCG-induced antitumor activity is not quite unclear, but the reduced efficacy of BCG immunotherapy in NK-cell-depleted mice compared with nondepleted mice, including both increased tumor growth and reduced survival, was reported.