Salmonella Breaks Tumor Immune Tolerance by Downregulating Tumor Programmed Death-Ligand 1 Expression

Abstract

Immunotherapy is becoming a popular treatment modality in combat against cancer, one of the world’s leading health problems. While tumor cells influence host immunity via expressing immune inhibitory signaling proteins, some bacteria possess immunomodulatory activities that counter the symptoms of tumors. The accumulation of Salmonella in tumor sites influences tumor protein expression, resulting in T cell infiltration. However, the molecular mechanism by which Salmonella activates T cells remains elusive. Many tumors have been reported to have high expressions of programmed death-ligand 1 (PD-L1), which is an important immune checkpoint molecule involved in tumor immune escape. In this study, Salmonella reduced the expression of PD-L1 in tumor cells. The expression levels of phospho-protein kinase B (P-AKT), phospho-mammalian targets of rapamycin (P-mTOR), and the phospho-p70 ribosomal s6 kinase (P-p70s6K) pathway were revealed to be involved in the Salmonella-mediated downregulation of PD-L1. In a tumor-T cell coculture system, Salmonella increased T cell number and reduced T cell apoptosis. Systemic administration of Salmonella reduced the expressions of PD-L-1 in tumor-bearing mice. In addition, tumor growth was significantly inhibited along with an enhanced T cell infiltration following Salmonella treatment. These findings suggest that Salmonella acts upon the immune checkpoint, primarily PD-L1, to incapacitate protumor effects and thereby inhibit tumor growth.

Salmonella alters heparanase expression and reduces tumor metastasis

“…The growth rate of tumor might be a critical factor involved Salmonella treatment. Furthermore, we have demonstrated that Salmonella can inhibit tumor growth in tumor-bearing mice [14,17]. We investigate the possible mechanism causing the regression.…”

“…choleraesuis (Smith) Weldin serovar Dublin (ATCC 15480)] was obtained from Bioresources Collection and Research Center (Hsinchu, Taiwan) [13]. As described above, a constitutively active AKT plasmid were used in this study [14][15][16]. The resveratrol and 4',6-Diamidino-2-Phenylindole (DAPI) a were purchased from Sigma-Aldrich (Sigma Aldrich, St. Louis, MO, USA).…”

Perspectives on Oncolytic Salmonella in Cancer Immunotherapy—A Promising Strategy

“…Data from these experiments demonstrated that Salmonella downregulated PD-L1 expression in a p-AKT, p-mTOR and p-p70S6K involved manner. As a result of reduced apoptosis, the T cell numbers rose ( 79 ). Salmonella also affects other immunosuppressive cells ( 60 ) in the TME.…”

“…Among them, the relationship between Salmonella and immune checkpoint has not received sufficient attention. Chen et al found the down-regulation of PD-L1 expression in a variety of mouse and human tumor cells treated with Salmonella , affects apoptosis of co-cultured PD-1-expression cells ( 79 ). However, PD-L1 is also expressed in other non-tumor cells in TME, such as stromal cells, myeloid-derived cells and infiltrating immune cells ( 169 , 175 ).…”

The roles of curcumin in regulating the tumor immunosuppressive microenvironment (Review)

“…Third, the lack of major histocompatibility complex class I on the surface of tumor cells can lead to the inability of the immune recognition of CD8+ cytotoxic T cells to mediate immune tolerance (63). In addition, upregulated expression of immunosuppressive ligands, such as programmed cell death-ligand 1, also mediates tumor immune tolerance (64). Subsequently, the immune cells in both innate and adaptive immunity become apoptotic due to the lack of stimulation of tumor-associated antigens and the inability to specifically recognize tumor cells, leading to the immune escape of tumors (65,66).…”