Abstract:Vaccinia viruses (VACV) are a novel class of immune-oncolytic therapeutics and their mechanism of action is based both on their capacity to replicate selectively in cancer cells and to elicit danger signals that can boost anti-tumor immunity. We recently reported that the intratumor expression of MLKL, a necroptosis inducing factor, generates a protective anti-tumor immunity. Here, we combined both approaches to test the use of VACV to deliver MLKL into the tumor. We generated VACV vectors expressing MLKL and … Show more
“…However, replication of the virus was strongly hindered within tumors (using the Renca model) due to massive pathway activation; conversely, our novel strategy of accumulating up to three deletions in VACV genes interfering with the TLR3-IRF3 pathway fully conserved the replication capacity in Renca tumors ( Figure 4 ). We have previously demonstrated the importance of VACV replication for activating an antitumor immune response, 26 which is discrepant to some previous reports. 45 Yet, virus replication leads to tumor cell lysis and release of tumor antigens, in addition to amplifying the initial dose administered and multiplying danger signals.…”
Section: Discussioncontrasting
confidence: 99%
“…The survival time of this model is shown in Figure 5 D. MVA was not included as a control in these experiments, as the antitumor activity of this virus is limited by its incapacity to productively replicate in tumor cells when compared to WR/TK−. 26 Figure 5 Increased in vivo antitumor activity of candidate oncolytic VACV with combination of gene deletions rescuing IRF3 activation (A–D) 5 × 10 5 tumor cells were subcutaneously implanted at day −9 on the flank of 6- to 8-week-old BALB/c mice (Renca tumors, A and B) or C57BL/6 mice (B16 tumors, C and D), and viruses were intratumorally administered at days 0 and 4 at a dose of 1 × 10 7 PFU/injection. PBS-injected mice served as controls.…”
Section: Resultsmentioning
confidence: 99%
“…For the construction of mutant viruses with accumulating gene deletions, the homologous recombination process was repeated with a different shuttle plasmid once the first deletion was confirmed. Viruses were purified as previously described 26 and titrated by a plaque assay in MA104 cells (for replication-competent VACV) or in CEF cells (for the MVA strain). The whole-genome sequences of the WR/TK− and WR/TK−/3Δ viruses were determined and analyzed using MinION technology (Laboratory for Functional Genome Analysis, LMU, Germany).…”
Section: Methodsmentioning
confidence: 99%
“… 24 , 25 However, the particular genetics of MVA are associated with a defective replication in mammalian cells, which greatly reduces its capacity for use as an oncolytic agent. 26 , 27 , 28 , 29 Thus, the generation of oncolytic VACV combining the capacity to activate the TLR3-IRF3 pathway with an efficient replication in cancer cells represents a major step toward an efficient VACV-based oncolytic therapy.…”
Recently, oncolytic vaccinia viruses (VACVs) have shown their potential to provide for clinically effective cancer treatments. The reason for this clinical usefulness is not only the direct destruction of infected cancer cells but also activation of immune responses directed against tumor antigens. For eliciting a robust antitumor immunity, a dominant T helper 1 (Th1) cell differentiation of the response is preferred, and such polarization can be achieved by activating the Toll-like receptor 3 (TLR3)-interferon regulatory factor 3 (IRF3) signaling pathway. However, current VACVs used as oncolytic viruses to date still encode several immune evasion proteins involved in the inhibition of this signaling pathway. By inactivating genes of selected regulatory virus proteins, we aimed for a candidate virus with increased potency to activate cellular antitumor immunity but at the same time with a fully maintained replicative capacity in cancer cells. The removal of up to three key genes (
C10L
,
N2L
, and
C6L
) from VACV did not reduce the strength of viral replication, both
in vitro
and
in vivo
, but resulted in the rescue of IRF3 phosphorylation upon infection of cancer cells. In syngeneic mouse tumor models, this activation translated to enhanced cytotoxic T lymphocyte (CTL) responses directed against tumor-associated antigens and neo-epitopes and improved antitumor activity.
“…However, replication of the virus was strongly hindered within tumors (using the Renca model) due to massive pathway activation; conversely, our novel strategy of accumulating up to three deletions in VACV genes interfering with the TLR3-IRF3 pathway fully conserved the replication capacity in Renca tumors ( Figure 4 ). We have previously demonstrated the importance of VACV replication for activating an antitumor immune response, 26 which is discrepant to some previous reports. 45 Yet, virus replication leads to tumor cell lysis and release of tumor antigens, in addition to amplifying the initial dose administered and multiplying danger signals.…”
Section: Discussioncontrasting
confidence: 99%
“…The survival time of this model is shown in Figure 5 D. MVA was not included as a control in these experiments, as the antitumor activity of this virus is limited by its incapacity to productively replicate in tumor cells when compared to WR/TK−. 26 Figure 5 Increased in vivo antitumor activity of candidate oncolytic VACV with combination of gene deletions rescuing IRF3 activation (A–D) 5 × 10 5 tumor cells were subcutaneously implanted at day −9 on the flank of 6- to 8-week-old BALB/c mice (Renca tumors, A and B) or C57BL/6 mice (B16 tumors, C and D), and viruses were intratumorally administered at days 0 and 4 at a dose of 1 × 10 7 PFU/injection. PBS-injected mice served as controls.…”
Section: Resultsmentioning
confidence: 99%
“…For the construction of mutant viruses with accumulating gene deletions, the homologous recombination process was repeated with a different shuttle plasmid once the first deletion was confirmed. Viruses were purified as previously described 26 and titrated by a plaque assay in MA104 cells (for replication-competent VACV) or in CEF cells (for the MVA strain). The whole-genome sequences of the WR/TK− and WR/TK−/3Δ viruses were determined and analyzed using MinION technology (Laboratory for Functional Genome Analysis, LMU, Germany).…”
Section: Methodsmentioning
confidence: 99%
“… 24 , 25 However, the particular genetics of MVA are associated with a defective replication in mammalian cells, which greatly reduces its capacity for use as an oncolytic agent. 26 , 27 , 28 , 29 Thus, the generation of oncolytic VACV combining the capacity to activate the TLR3-IRF3 pathway with an efficient replication in cancer cells represents a major step toward an efficient VACV-based oncolytic therapy.…”
Recently, oncolytic vaccinia viruses (VACVs) have shown their potential to provide for clinically effective cancer treatments. The reason for this clinical usefulness is not only the direct destruction of infected cancer cells but also activation of immune responses directed against tumor antigens. For eliciting a robust antitumor immunity, a dominant T helper 1 (Th1) cell differentiation of the response is preferred, and such polarization can be achieved by activating the Toll-like receptor 3 (TLR3)-interferon regulatory factor 3 (IRF3) signaling pathway. However, current VACVs used as oncolytic viruses to date still encode several immune evasion proteins involved in the inhibition of this signaling pathway. By inactivating genes of selected regulatory virus proteins, we aimed for a candidate virus with increased potency to activate cellular antitumor immunity but at the same time with a fully maintained replicative capacity in cancer cells. The removal of up to three key genes (
C10L
,
N2L
, and
C6L
) from VACV did not reduce the strength of viral replication, both
in vitro
and
in vivo
, but resulted in the rescue of IRF3 phosphorylation upon infection of cancer cells. In syngeneic mouse tumor models, this activation translated to enhanced cytotoxic T lymphocyte (CTL) responses directed against tumor-associated antigens and neo-epitopes and improved antitumor activity.
“…The role of RIP3 (necroptosis-related molecules) in increasing myeloid cell-induced adaptive immune suppression and improving the proliferation of premalignant intestinal epithelial cells (IECs) was demonstrated by Liu’s research ( Liu et al, 2019 ). Hoecke used a mouse model to prove that the necroptosis mediator MLKL has an antitumor immunity effect ( Van Hoecke et al, 2020 ). Several studies have suggested that necroptosis plays an essential role in tumors, but the mechanism is still not fully defined.…”
Colon cancer (CC) is one of the most frequent malignancies in the world, with a high rate of morbidity and death. In CC, necroptosis and long noncoding RNA (lncRNAs) are crucial, but the mechanism is not completely clear. The goal of this study was to create a new signature that might predict patient survival and tumor immunity in patients with CC. Expression profiles of necroptosis-related lncRNAs in 473 patients with CC were retrieved from the TCGA database. A consensus clustering analysis based on differentially expressed (DE) genes and a prognostic model based on least absolute shrinkage and selection operator (LASSO) regression analysis were conducted. Clinicopathological correlation analysis, expression difference analysis, PCA, TMB, GO analysis, KEGG enrichment analysis, survival analysis, immune correlation analysis, prediction of clinical therapeutic compounds, and qRT–PCR were also conducted. Fifty-six necroptosis-related lncRNAs were found to be linked to the prognosis, and consensus clustering analysis was performed. There were substantial variations in survival, immune checkpoint expression, clinicopathological correlations, and tumor immunity among the different subgroups. Six lncRNAs were discovered, and patients were split into high-risk and low-risk groups based on a risk score generated using these six lncRNAs. The survival time of low-risk patients was considerably longer than that of high-risk patients, indicating that these lncRNAs are directly associated with survival. The risk score was associated with the tumor stage, infiltration depth, lymph node metastasis, and distant metastasis. After univariate and multivariate Cox regression analysis, the risk score and tumor stage remained significant. Cancer- and metabolism-related pathways were enriched by KEGG analyses. Immune infiltration was shown to differ significantly between high- and low-risk patients in a tumor immunoassay. Eight compounds were screened out, and qRT–PCR confirmed the differential expression of the six lncRNAs. Overall, in CC, necroptosis-related lncRNAs have an important function, and the prognosis of patients with CC can be predicted by these six necroptosis-related lncRNAs. They may be useful in the future for customized cancer therapy.
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