<i>Salmonella</i> inhibits tumor angiogenesis by downregulation of vascular endothelial growth factor

Tu, Dom‐Gene; Chang, Wen‐Wei; Lin, Song-Tao; Kuo, Chun-Yu; Tsao, Yu-Tzu; Lee, Che‐Hsin

doi:10.18632/oncotarget.7038

Cited by 46 publications

(47 citation statements)

References 38 publications

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“…Similar results could be found in different strains of Salmonella [10]. In addition to that, Salmonella also inhibited angiogenesis in both murine melanoma and breast cancer models, which is another crucial mechanism to incapacitate pro-tumor activities [28]. Even in this study, using the same Salmonella wherein we investigated the relationship between Salmonella-infected tumor and the immune cells, we are starting to understand how the bacteria targeting tumors alters the tumor microenvironment in a multitude of ways and how these changes at the molecular level could positively affect immune cells to act against the tumor.…”

Section: Discussionsupporting

confidence: 84%

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

Chen

Pangilinan

Lee

2019

Cancers

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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.

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Section: Discussionsupporting

confidence: 84%

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

Chen

Pangilinan

Lee

2019

Cancers

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“…immune therapies currently in preclinical development have shown efficacy by altering the microenvironment in ways other than directly killing tumor cells. These include therapies using Toxoplasma gondii, Salmonella, Semliki Forest virus, and inactivated modified vaccinia virus Ankara, all of which have been tested preclinically in a B16 melanoma model and all of which function by altering the cytokine milieu, increasing leukocyte infiltration of tumors, and/or increasing antigen recognition or function of CD8 ϩ T cells (27)(28)(29)(30)(31)(32)(33).…”

mentioning

confidence: 99%

“…Given the disparate effects of CMV in various settings, we wished to define the mechanism by which MCMV delayed tumor growth using the B16-F0 melanoma model. This was a particularly attractive model because B16 melanomas are notoriously aggressive, are resistant to immune therapies, and have been used extensively for exploring interventions that overcome this resistance, such as administering pathogens that kill tumor cells or modulate the immune environment (27)(28)(29)(30)(31)(32)(33). Moreover, B16-F0 tumors are immunologically "cold," containing few infiltrating immune cells in the absence of interventions.…”

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confidence: 99%

Murine Cytomegalovirus Infection of Melanoma Lesions Delays Tumor Growth by Recruiting and Repolarizing Monocytic Phagocytes in the Tumor

Wilski

Casale

Purwin

et al. 2019

J Virol

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Cytomegalovirus (CMV) is a ubiquitous betaherpesvirus that infects many different cell types. Human CMV (HCMV) has been found in several solid tumors, and it has been hypothesized that it may promote cellular transformation or exacerbate tumor growth. Paradoxically, in some experimental situations, murine CMV (MCMV) infection delays tumor growth. We previously showed that wild-type MCMV delayed the growth of poorly immunogenic B16 melanomas via an undefined mechanism. Here, we show that MCMV delayed the growth of these immunologically “cold” tumors by recruiting and modulating tumor-associated macrophages. Depletion of monocytic phagocytes with clodronate completely prevented MCMV from delaying tumor growth. Mechanistically, our data suggest that MCMV recruits new macrophages to the tumor via the virus-encoded chemokine MCK2, and viruses lacking this chemokine were unable to delay tumor growth. Moreover, MCMV infection of macrophages drove them toward a proinflammatory (M1)-like state. Importantly, adaptive immune responses were also necessary for MCMV to delay tumor growth as the effect was substantially blunted in Rag-deficient animals. However, viral spread was not needed and a spread-defective MCMV strain was equally effective. In most mice, the antitumor effect of MCMV was transient. Although the recruited macrophages persisted, tumor regrowth correlated with a loss of viral activity in the tumor. However, an additional round of MCMV infection further delayed tumor growth, suggesting that tumor growth delay was dependent on active viral infection. Together, our results suggest that MCMV infection delayed the growth of an immunologically cold tumor by recruiting and modulating macrophages in order to promote anti-tumor immune responses. IMPORTANCE Cytomegalovirus (CMV) is an exciting new platform for vaccines and cancer therapy. Although CMV may delay tumor growth in some settings, there is also evidence that CMV may promote cancer development and progression. Thus, defining the impact of CMV on tumors is critical. Using a mouse model of melanoma, we previously found that murine CMV (MCMV) delayed tumor growth and activated tumor-specific immunity although the mechanism was unclear. We now show that MCMV delayed tumor growth through a mechanism that required monocytic phagocytes and a viral chemokine that recruited macrophages to the tumor. Furthermore, MCMV infection altered the functional state of macrophages. Although the effects of MCMV on tumor growth were transient, we found that repeated MCMV injections sustained the antitumor effect, suggesting that active viral infection was needed. Thus, MCMV altered tumor growth by actively recruiting macrophages to the tumor, where they were modulated to promote antitumor immunity.

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“…Hence, current researches focused on supportive role of Salmonella or resveratrol in chemoresistance, anti-angiogenesis and immune modulation etc. rather than their direct toxicity to tumor cells 24 , 26 , 35 - 38 . Here, we identified the potential of resveratrol and Salmonella that regulating Cx43 and IDO.…”

Section: Discussionmentioning

confidence: 99%

The inhibition of indoleamine 2, 3-dioxygenase 1 by connexin 43

et al. 2017

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Upregulation of connexin 43 (Cx43) showed potential in enhancing immune surveillance that was suppressed in the tumor microenvironment. The expression of indoleamine 2, 3-dioxygenase (IDO) is one of the crucial factors contributing to tumor immune tolerance by depletion of tryptophan and IDO-mediated tryptophan metabolites. Here, we aim to investigate the role of Cx43 in IDO production in murine tumor by using Cx43 inducers. Resveratrol (trans-3, 5, 4 '-trihydroxystilbene) is a natural plant-derived polyphenol possessing positive effect against cancer. Salmonella enterica serovar choleraesuis (S.C.) was proved to target and inhibit tumor growth. Both of them regulated Cx43 expression in tumor cells and led to either chemosensitizing or immune-activating. In this study, the correlation between Cx43 and IDO were determined by the treatment of resveratrol and S.C. Our data showed an increase in Cx43 while IDO protein and IDO-mediated inhibited effects on T cell decreased after tumor cells are given with resveratrol and S.C. treatments. All of which could be inhibited once the expression of Cx43 was blocked. Cx43 involved in IDO regulation might be useful in developing IDO-targeted cancer immune therapy.

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Salmonella inhibits tumor angiogenesis by downregulation of vascular endothelial growth factor

Cited by 46 publications

References 38 publications

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

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

Murine Cytomegalovirus Infection of Melanoma Lesions Delays Tumor Growth by Recruiting and Repolarizing Monocytic Phagocytes in the Tumor

The inhibition of indoleamine 2, 3-dioxygenase 1 by connexin 43

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