Immune adjuvant effect of a<i>Toxoplasma gondii</i>profilin-like protein in autologous whole-tumor-cell vaccination in mice

Pyo, Kyoung‐Ho; Lee, You Won; Lim, Sun Min; Shin, Eun Hee

doi:10.18632/oncotarget.12316

Cited by 19 publications

(17 citation statements)

References 45 publications

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“…According to the results of an earlier study, T. gondii infection is generally controlled by a strong Th1-type immune response via the cytokines IL-12p70, TNF-α, and IFN-γ. However, the recruited monocyte population is converted to an anti-inflammatory phenotype in order to restrain excessive immune responses during infection of T. gondii strain RH ( 3 – 6 , 12 , 14 , 21 , 22 ). On the other hand, the time of infection for the change in microglial cells and inflammatory responses as a cause of CI of the brain infected with strain ME49 it is not well defined.…”

Section: Discussionmentioning

confidence: 99%

Characteristics of Infection Immunity Regulated by Toxoplasma gondii to Maintain Chronic Infection in the Brain

et al. 2018

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To examine the immune environment of chronic Toxoplasma gondii infection in the brain, the characteristics of infection-immunity (premunition) in infection with T. gondii strain ME49 were investigated for 12 weeks postinfection (PI). The results showed that neuronal cell death, microglia infiltration and activation, inflammatory and anti-inflammatory cytokine expression, Stat1 phosphorylation, and microglia activation and inflammatory gene transcripts related to M1 polarization in the brain were increased during the acute infection (AI) stage (within 6 weeks PI), suggesting that innate and cellular inflammatory response activation and neurodegeneration contributed to excessive inflammatory responses. However, these immune responses decreased during the chronic infection (CI) stage (over 6 weeks PI) with reductions in phosphorylated STAT1 (pSTAT1) and eosinophilic neurons. Notably, increases were observed in transcripts of T-cell exhaustion markers (TIM3, LAG3, KLRG1, etc.), suppressor of cytokines signaling 1 protein (SOCS1), inhibitory checkpoint molecules (PD-1 and PD-L1), and Arg1 from the AI stage (3 weeks PI), implying active immune intervention under the immune environment of M1 polarization of microglia and increases in inflammatory cytokine levels. However, when BV-2 microglia were stimulated with T. gondii lysate antigens (strain RH or ME49) in vitro, nitrite production increased and urea production decreased. Furthermore, when BV-2 cells were infected by T. gondii tachyzoites (strain RH or ME49) in vitro, nitric oxide synthase and COX-2 levels decreased, whereas Arg1 levels significantly increased. Moreover, Arg1 expression was higher in ME49 infection than in RH infection, whereas nitrite production was lower in ME49 infection than in RH infection. Accordingly, these results strongly suggest that immune triggering of T. gondii antigens induces M1 polarization and activation of microglia as well as increase NO production, whereas T. gondii infection induces the inhibition of harmful inflammatory responses, even with M1 polarization and activation of microglia and Th1 inflammatory responses, suggesting a host–parasite relationship through immune regulation during CI. This is a characteristic of infection immunity in infection with T. gondii in the central nervous system, and SOCS1, a negative regulator of toxoplasmic encephalitis, may play a role in the increase in Arg1 levels to suppress NO production.

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Section: Discussionmentioning

confidence: 99%

Characteristics of Infection Immunity Regulated by Toxoplasma gondii to Maintain Chronic Infection in the Brain

et al. 2018

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“…T. gondii has shown anticancer effects against various cancer types and diverse antigenic proteins [21][22][23]. As a biological property, T. gondii evades or regulates host immunity to facilitate proliferation and maintenance of its life cycle [24,25].…”

Section: Discussionmentioning

confidence: 99%

“…As a biological property, T. gondii evades or regulates host immunity to facilitate proliferation and maintenance of its life cycle [24,25]. This control of immunity during T. gondii infection has stimulated multiple investigations related to other immune diseases; as a result, T. gondii proteins have been considered therapeutic agents for other incurable diseases [10,14,[21][22][23][24][25]. Regarding the original biological properties of GRA16 used in this study, dense granule proteins, such as GRA16, within the secretory vesicles of T. gondii participate in a membranous nanotubular network in parasitophorous vacuoles (PVs) that maintain intracellular parasitism in host cells [10,13,14].…”

Section: Discussionmentioning

confidence: 99%

Toxoplasma GRA16 Inhibits NF-κB Activation through PP2A-B55 Upregulation in Non-Small-Cell Lung Carcinoma Cells

Seo

Kim

Shin

et al. 2020

IJMS

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Nuclear factor kappa B (NF-κB) activation is a well-known mechanism by which chemoresistance to anticancer agents is reported. It is well-known that irinotecan as a chemotherapeutic drug against non-small-cell lung carcinoma (NSCLC) has limited anticancer effect due to NF-κB activation. In this study, we propose the novel role of GRA16, a dense granule protein of Toxoplasma gondii, as an anticancer agent to increase the effectiveness of chemotherapy via the inhibition of NF-κB activation. To demonstrate this, H1299 cells were stably transfected with GRA16. The anticancer effects of GRA16 were demonstrated as a reduction in tumor size in a mouse xenograft model. GRA16 directly elevated B55 regulatory subunit of protein phosphatase 2A (PP2A-B55) expression in tumor cells, thereby decreasing GWL protein levels and ENSA phosphorylation. This cascade, in turn, induced PP2A-B55 activation and suppressed AKT/ERK phosphorylation and cyclin B1 levels, suggesting reduced cell survival and arrested cell cycle. Moreover, PP2A-B55 activation and AKT phosphorylation inhibition led to NF-κB inactivation via the reduction in inhibitory kappa B kinase beta (IKKβ) levels, de-phosphorylation of inhibitor of kappa B alpha (IκBα), and reduction in the nuclear transit of NF-κB p65. Furthermore, this molecular mechanism was examined under irinotecan treatment. The PP2A-B55/AKT/NF-κB p65 pathway-mediated anticancer effects were only induced in the presence of GRA16, but not in the presence of irinotecan. Moreover, GRA16 synergistically promoted the anticancer effects of irinotecan via the induction of the sub-G1 phase and reduction of cell proliferation. Collectively, irinotecan and GRA16 co-treatment promotes the anticancer effects of irinotecan via NF-κB inhibition and cell cycle arrest induced by GRA16, subsequently increasing the chemotherapeutic effect of irinotecan to NSCLC cells via NF-κB inhibition.

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“…10,11 Briefly, the immunomodulatory activities of T gondii are mediated by infection as well as several T gondii-specific molecules such as rhoptry proteins (ROP), dense granule proteins (GRA), T gondii profilin-like protein (TgPLP) and the lysate antigenic proteins. 10,11 Briefly, the immunomodulatory activities of T gondii are mediated by infection as well as several T gondii-specific molecules such as rhoptry proteins (ROP), dense granule proteins (GRA), T gondii profilin-like protein (TgPLP) and the lysate antigenic proteins.…”

Section: Introductionmentioning

confidence: 99%

“…Toxoplasma gondii (T gondii) is an intracellular parasite that infects multiple organs and tissues in acute infection and the brain in chronic infection 9,10 and regulates the host immunity for its survival during infection. 10,11 Briefly, the immunomodulatory activities of T gondii are mediated by infection as well as several T gondii-specific molecules such as rhoptry proteins (ROP), dense granule proteins (GRA), T gondii profilin-like protein (TgPLP) and the lysate antigenic proteins. 9,10 Thus, our objective was to determine the intermediate events between HAUSP inhibition and p53 stabilization and also the anticancer effect.…”

Section: Introductionmentioning

confidence: 99%

Increase in the nuclear localization of PTEN by the Toxoplasma GRA16 protein and subsequent induction of p53‐dependent apoptosis and anticancer effect

Kim

Seo

Shin

et al. 2019

J Cellular Molecular Medi

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This study investigated the efficacy of Toxoplasma GRA16, which binds to herpes virus‐associated ubiquitin‐specific protease (HAUSP), in anticancer treatment, and whether the expression of GRA16 in genetically modified hepatocellular carcinoma (HCC) cells (GRA16‐p53‐wild HepG2 and GRA16‐p53‐null Hep3B) regulates PTEN because alterations in phosphatase and tensin homologue (PTEN) and p53 are vital in liver carcinogenesis and the abnormal p53 gene appears in HCC. For this purpose, we established the GRA16 cell lines using the pBABE retrovirus system, assessed the detailed mechanism of PTEN regulation in vitro and established the anticancer effect in xenograft mice. Our study showed that cell proliferation, antiapoptotic factors, p‐AKT/AKT ratio, cell migration and invasive activity were decreased in GRA16‐stable HepG2 cells. Conversely, the apoptotic factors PTEN and p53 and apoptotic cells were elevated in GRA16‐stable HepG2 cells but not in Hep3B cells. The change in MDM2 was inconspicuous in both HepG2 and Hep3B; however, the PTEN level was remarkably elevated in HepG2 but not in Hep3B. HAUSP‐bound GRA16 preferentially increased p53 stabilization by the nuclear localization of PTEN rather than MDM2‐dependent mechanisms. These molecular changes appeared to correlate with the decreased tumour mass in GRA16‐stable‐HepG2 cell‐xenograft nude mice. This study establishes that GRA16 is a HAUSP inhibitor that targets the nuclear localization of PTEN and induces the anticancer effect in a p53‐dependent manner. The efficacy of GRA16 could be newly highlighted in HCC treatment in a p53‐dependent manner.

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Immune adjuvant effect of aToxoplasma gondiiprofilin-like protein in autologous whole-tumor-cell vaccination in mice

Cited by 19 publications

References 45 publications

Characteristics of Infection Immunity Regulated by Toxoplasma gondii to Maintain Chronic Infection in the Brain

Characteristics of Infection Immunity Regulated by Toxoplasma gondii to Maintain Chronic Infection in the Brain

Toxoplasma GRA16 Inhibits NF-κB Activation through PP2A-B55 Upregulation in Non-Small-Cell Lung Carcinoma Cells

Increase in the nuclear localization of PTEN by the Toxoplasma GRA16 protein and subsequent induction of p53‐dependent apoptosis and anticancer effect

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