Use of Salmonella Bacteria in Cancer Therapy: Direct, Drug Delivery and Combination Approaches

Abstract

Over the years, conventional cancer treatments, such as chemotherapy with only a limited specificity for tumors, have undergone significant improvement. Moreover, newer therapies such as immunotherapy have undergone a revolution to stimulate the innate as well as adaptive immune responses against the tumor. However, it has been found that tumors can be selectively colonized by certain bacteria, where they can proliferate, and exert direct oncolytic effects as well as stimulating the immune system. Bacterial-mediated cancer therapy (BMCT) is now one example of a hot topic in the antitumor field. Salmonella typhimurium is a Gram-negative species that generally causes self-limiting gastroenteritis in humans. This species has been designed and engineered in order to be used in cancer-targeted therapeutics. S. typhimurium can be used in combination with other treatments such as chemotherapy or radiotherapy for synergistic modification of the tumor microenvironment. Considerable benefits have been shown by using engineered attenuated strains for the diagnosis and treatment of tumors. Some of these treatment approaches have received FDA approval for early-phase clinical trials. This review summarizes the use of Salmonella bacteria for cancer therapy, which could pave the way towards routine clinical application. The benefits of this therapy include an automatic self-targeting ability, and the possibility of genetic manipulation to produce newly engineered attenuated strains. Nevertheless, Salmonella-mediated anticancer therapy has not yet been clinically established, and requires more research before its use in cancer treatment.

Keywords: Salmonella species; bacteria-mediated cancer therapy; cancer; drug delivery; therapy.

Figure 1

Major antitumor mechanisms stimulated by Salmonella (S. typhimurium). Both bacteria-mediated direct cytotoxicity and immune system-mediated indirect tumor cell death have been proposed. (A) In the tumor microenvironment, bacterial infection inhibits the growth of the tumor and results in considerable cell death. (B) The recognition of pathogen-related molecular patterns (PAMP) on the bacterial cells by receptors expressed on immune cells, triggers the release of cytokines and the recruitment of leukocytes that can initiate anti-tumor immune responses (–31). (C) S. typhimurium uses a Type III secretion system which leads to the release of different factors into cancer cells, and the bacteria can also be internalized and undergo intra-cellular replication (32, 33). (C.I) Cell stress responses are induced by invasive Salmonella cells mediated via danger-associated molecular patterns (DAMP) that also act as signals to the immune system. (C.II) At the same time, this process together with the released cytokines leads to the presentation of bacterial antigens as well as cancer specific antigens, to the adaptive immune system leading to the production of cancer-antigen specific T-cells that can recognize and kill the cancer cells as well as the bacteria (34). An immunological synapse occurs between the bacteria, the cancer cells and the host dendritic cells leading to cross-presentation of tumor antigens, resulting in an antigen-specific anti-cancer immune response (35, 36). (C.III) Salmonella bacteria have the potential to directly cause cancer cell death through induction of apoptosis or pyroptosis. Pyroptosis is a form of programmed inflammatory cell death, characterized by activation of caspase 1 and the inflammasomes, and secretion of IL-1β as well as IL-18. It is also characterized by cell rounding and detachment, reorganization of the cytoskeleton, deformation of the nucleus, together with rupture of the cell membrane and release of additional inflammatory signals (–39). The description of pyroptosis first took place in macrophages that died rapidly under certain conditions, which is particularly important in cancer immunotherapy, since tumor-associated macrophages (TAM) are considered to possess immune-suppressive properties. Reduction of TAMs can be considered as another aspect of the S. typhimurium anti-tumor activity. The dead cancer cells can liberate tumor antigens, while the surrounding cancer cells are infected by the released bacteria. (C.IV) During pyroptosis, immune cell recruitment and activation can be triggered by the pro-inflammatory cytokines IL-1β and IL-18 (37, 38, 40). (D) The convergence of several different mechanisms enables recognition of tumor antigens, leading to stimulation of both antigen-dependent and antigen-independent cell killing. The proteasomal degradation of S. typhimurium proteins within the cancer cell cytosol, leads to production of bacterial peptides that can be presented to cytotoxic lymphocytes through MHC I (34, 41). This figure is adapted from (42).