Synergistic anti-suppressor effect of mini cells prepared from Salmonella typhimurium and mitomycin C in EL 4-bearing mice

Abstract

The subcutaneous growth of EL4 cells was significantly accelerated when they were injected together with spleen cells collected from mice which had received EL4 cells SC 14 days previously, and all mice died within 18 days after receiving this mixture; 80% of mice which received a mixture of EL4 and spleen cells collected immediately after EL4 graft survived over 40 days. Spleen cells collected 14 days after EL4 graft suppressed the blastogenic responses of normal spleen lymphocytes to concanavalin A, pokeweed mitogen, and lipopolysaccharide of Escherichia coli in a mixed culture system. Acceleration of tumor growth was retarded when EL4 cells were injected together with spleen cells from EL4-bearing mice treated with both Salmonella typhimurium mini-cells and mitomycin C, and 60% of mice survived over 40 days. Blastogenic responses of normal spleen lymphocytes mixed with spleen cells from EL4-bearing mice treated with both mini-cells and mitomycin C were restored almost to control levels. The results suggest that combination treatment with mini-cells and mitomycin C synergistically inhibits the induction of suppressor cells in EL4-bearing mice.

Recombinant Attenuated Salmonella enterica as a Delivery System of Heterologous Molecules in Cancer Therapy

“…Initial immunotherapeutic studies of Salmonella enterica were conducted by Kurashige S. et al, using minicells (vesicles with no genomic DNA) in murine models (sarcoma [ 99 ] and T-cell lymphoma [ 100 ]). The results showed that the administration of minicells activated the innate immune response and promoted the eradication of transformed cells.…”

Infection by <i>Salmonella enterica</i> Promotes or Demotes Tumor Development

“…In the tumor microenvironment, Salmonella enterica induces the reversal of the suppressor environment by facilitating the expression of soluble mediators such as inducible nitric oxide synthase (iNOS) and interferon-γ (IFN-γ), molecules that promote antitumor activity and inhibit the expression of immunosuppressive factors such as arginase-1, interleukin-4 (IL-4), transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) [8,87]; also, Salmonella enterica decreases the activity of myeloidderived suppressor cells (MDSCs) [88] and promotes the recruitment of natural killer (NK) cells [89], neutrophils [74], macrophages [87] and T [90] and B lymphocytes [91]. The first studies describing the immunotherapeutic antitumor properties of Salmonella enterica were reported by Kurashige S. et al; whereby with the use of mini cells (vesicles with no genomic DNA) obtained from S. typhimurium and administered to a murine sarcoma model [92] and T-cell lymphoma [93], and macrophage activity was restored in the tumor microenvironment and helped eliminate the tumor.…”

Cancer Immunotherapy: Priming the Host Immune Response with Live Attenuated Salmonella enterica

“…In the tumor microenvironment, immunosurveillance evasion mechanisms prevent the eradication of tumor cells [ 2 ] and represent a barrier that Salmonella enterica must overcome when used as an immunotherapeutic agent. The first studies describing the antitumor immunotherapeutic properties of Salmonella enterica were conducted by Kurashige et al, using minicells (vesicles with no genomic DNA) obtained from Salmonella Typhimurium, and evaluated in two different murine models (sarcoma [ 74 ] and T-cell lymphoma [ 75 ]); they observed that the administration of these minicells restored macrophage activity in the tumor microenvironment, promoting tumor elimination. Recent studies have reported that some of the mechanisms that could use the bacterium to eliminate the tumor cells once it is in the tumor microenvironment involved enhance the expression of soluble mediators such as inducible nitric oxide synthase (iNOS) and interferon γ (IFN- γ ) and also inhibit the expression of immunosuppressive factors such as arginase-1, interleukin-4 (IL-4), transforming growth factor- β (TGF- β ), and vascular endothelial growth factor (VEGF) [ 19 ] ( Figure 2(a) ).…”