Tlr7 Agonist in Combination With
            <i>Salmonella</i>
            as an Effective Antimelanoma Immunotherapy

Vola, Magdalena; Mónaco, Amy; Bascuas, Thais; Rimsky, Geraldine; Agorio, Caroline; Chabalgoity, José A.; Moreno, Marı́a

doi:10.2217/imt-2017-0188

Cited by 12 publications

(9 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

mentioning

confidence: 99%

mentioning

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

View full text Add to dashboard Cite

show abstract

“…We have previously developed LVR01, an attenuated Salmonella enterica serovar Typhimurium, that showed to be safe as vaccine vector in many animal models ( Chabalgoity et al, 2000 ; Petavy et al, 2008 ; Goni et al, 2015 ; Grille et al, 2014 ; Kramer et al, 2015 ; Bascuas et al, 2018 ; Vola et al, 2018 ; Chilibroste et al, 2021 ; Mónaco et al, 2022 ). Besides, it holds great potential as a vaccine vector and tool for cancer immunotherapies ( Chabalgoity et al, 2000 ).…”

Section: Introductionmentioning

confidence: 99%

Salmonella-induced immune response reduces recurrence and tumor dissemination in preclinical melanoma model

Mónaco

Plata²,

Chilibroste³

et al. 2022

Current Research in Immunology

Self Cite

View full text Add to dashboard Cite

“…Attenuated S. typhimurium that is defective in ppGpp (ΔppGpp S. typhimurium ) synthesis has tumor-targeting ability and significantly suppresses tumor growth (Cao et al 2016; Yoon et al 2018; Vola et al 2018). Colonization and subsequent proliferation of ΔppGpp S. typhimurium within tumor tissues induces infiltration of immune cells, such as neutrophils, macrophages, and dendritic cells, which then secrete pro-inflammatory cytokines, such as IL-1β, which contribute to anti-cancer efficacy (Yu 2018; Qu et al 2012; Palsson-McDermott et al 2015; Kim et al 2015).…”

Section: Introductionmentioning

confidence: 99%

Secreting-lux/pT-ClyA engineered bacteria suppresses tumor growth via interleukin-1β in two pathways

Feng

Jiang

et al. 2019

AMB Expr

View full text Add to dashboard Cite

Engineered Salmonella typhimurium (S.t-ΔpGlux/pT-ClyA) and attenuated Salmonella typhimurium (SL: Salmonella typhimurium with a defect in the synthesis of guanine 5′-diphosphate-3′-diphosphate) exhibit similar tumor targeting capabilities (Kim et al. in Theranostics 5:1328–1342, 2015; Jiang et al. in Mol Ther 18:635–642, 2013), but S.t-ΔpGlux/pT-ClyA exerts superior tumor suppressive effects. The aim of this study was to investigate whether S.t-ΔpGlux/pT-ClyA inhibits colon cancer growth and recurrence by promoting increased IL-1β production. The CT26 tumor mouse model was used, and mice were treated in the following ways: PBS, S.t-ΔpGlux/pT-ClyA(+) + IL-1βAb, SL, S.t-ΔpGlux/pT-ClyA(−), and S.t-ΔpGlux/pT-ClyA(+). Dynamic evaluation of the efficacy of S.t-ΔpGlux/pT-ClyA in the treatment of colon cancer was assessed by MRI. Western blot, immunofluorescence and flow cytometry analysis were used to investigate IL-1β-derived cells and IL-1β expression on tumor cells and immune cells to analyze the regulatory mechanism. IL-1β levels in tumors colonized by S.t-ΔpGlux/pT-ClyA were significantly increased and maintained at high levels compared to control treatments. This increase caused tumors to subside without recurrence. We examined the immune cells mediating S.t-ΔpGlux/pT-ClyA-induced tumor suppression and examined the major cell types producing IL-1β. We found that macrophages and dendritic cells were the primary IL-1β producers. Inhibition of IL-1β in mice treated with S.t-ΔpGlux/pT-ClyA using an IL-1β antibody caused tumor growth to resume. This suggests that IL-1β plays an important role in the treatment of cancer by S.t-ΔpGlux/pT-ClyA. We found that in St-ΔpGlux/pT-ClyA-treated tumors, expression of molecules involved in signaling pathways, such as NLRP3, ASC, Caspase1, TLR4, MyD88, NF-kB and IL-1β, were upregulated, while in ΔppGpp S. typhimurium treated animals, TLR4, MyD88, NF-kB and IL-1β were upregulated with NLRP3, ASC, and Caspase1 being rarely expressed or not expressed at all. Using S.t-ΔpGlux/pT-ClyA may simultaneously activate TLR4 and NLRP3 signaling pathways, which increase IL-1β expression and enhance inhibition of colon cancer growth without tumor recurrence. This study provides a novel platform for treating colon cancer.

show abstract

Tlr7 Agonist in Combination With Salmonella as an Effective Antimelanoma Immunotherapy

Abstract: Salmonella LVR01 immunotherapy in combination with imiquimod is a novel approach that could be considered as an effective antimelanoma therapy.

Cited by 12 publications

References 48 publications

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

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

Salmonella-induced immune response reduces recurrence and tumor dissemination in preclinical melanoma model

Secreting-lux/pT-ClyA engineered bacteria suppresses tumor growth via interleukin-1β in two pathways

Contact Info

Product

Resources

About