Oncolytic biomineralized bacteria for tumor immunotherapy
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ABSTRACT:
PROVIDER: PRJNA868767 | ENA |
REPOSITORIES: ENA
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Project description:Bacteria-based cancer immunotherapy, dated back to Coley’s toxins (inactivated bacteria) in 1893, has recently regained substantial attentions, usually by using attenuated bacteria to transform immune-silent “cold” tumors into immune-inflamed “hot” ones. However, while inactivated bacteria showed limited antitumor efficacy, attenuated live bacteria often possessed significant safety risks. Herein, by biomineralizing growth of manganese dioxide on the surface of paraformaldehyde-fixed gram-negative Salmonella typhimurium (S. typhimurium), we obtained MnO2-coated fixed S. typhimurium (M@F.S), which showed potent immune-stimulating effects via activating multiple pathways including Toll-like receptors (TLRs), cyclic GMP-AMP Synthase (cGAS)-stimulator of interferon genes (STING) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs). Single intratumoral administration of M@F.S at safe doses resulted in surprisingly strong efficacies in suppressing various types of mouse tumor models and a rabbit cancer model, and the cured mice and rabbits gained immune memory to reject re-challenged tumors. An abscopal antitumor effect was also observed, suggesting systemic antitumor immunity triggered by local injection of M@F.S. The antitumor mechanisms of M@F.S were preliminarily demonstrated to be innate immune activation initiated by multiple signaling pathways, followed by subsequent activation of tumor-specific immune responses, together with the modulation of immunosuppressive tumor microenvironment. We further demonstrated the efficacy of biomineralized bacteria in inhibiting an orthotopic breast tumor model established on tree shrews, an alternative animal model to primates with better clinical relevance. Such oncolytic biomineralized bacteria could be a potent yet safe immunotherapeutic agent for treatment of various solid tumors.
2024-08-01 | GSE211069 | GEO
Project description:Oncolytic viruses (OV) are promising forms of immunotherapy that have demonstrated clinical benefit in difficult-to-treat cancers such as metastatic melanoma. However, their adoption in other malignancies has been limited, in part, due to poorly understood mechansims of therapeutic resistance. Here, bulk RNA-seq was performed on oncolytic vaccinia virus-sensitive and -resistant murine head and neck squamous cell carcinomas (MEERvvS and MEERvvR, respectively) to explore potential means of OV resistance. These results corroborated a potential role for TGF-beta mediated stabilization of immunosuppressive regulatory T cells in the tumor microenvironment of OV-resistant MEERvvR-bearing mice. Subsequently, treatment with oncolytic vaccinia virus engineered to expess a dominant negative TGF-β signaling inhibitor (VVtgfbi) restored sensitivity to OV-mediated cell death among MEERvvR tumors. Single-cell RNA seq performed on CD45+ immune cells isolated from tumors suggests TGF-β inhibition may also reduce the presence and activity of myeloid-derived suppressor cell populations within the tumor microenvironment.
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Project description:We constructed a chimeric oncolytic adenovirus which is a novel broad-spectrum anticancer product with multiple mechanisms of synergistic and potentiated immunotherapy
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Project description:We constructed a chimeric oncolytic adenovirus which is a novel broad-spectrum anticancer product with multiple mechanisms of synergistic and potentiated immunotherapy
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Project description:The oncolytic effect of virotherapy derives from the intrinsic capability of the applied virus in selectively infecting and killing tumor cells. Although oncolytic viruses of various constructions have been shown to efficiently infect and kill tumor cells in vitro, the efficiency of these viruses to exert the same effect on tumor cells within tumor tissues in vivo has not been extensively investigated. Here we report our studies using single-cell RNA sequencing to comprehensively analyze the gene expression profile of tumor tissues following herpes simplex virus 2-based oncolytic virotherapy. Our data revealed the extent and cell types within the tumor microenvironment that could be infected by the virus. Moreover, we observed changes in the expression of cellular genes, including antiviral genes, in response to viral infection. One notable gene found to be upregulated significantly in oncolytic virus-infected tumor cells was Gadd45g, which is desirable for optimal virus replication. These results not only help reveal the precise infection status of the oncolytic virus in vivo, but also provide insight that may lead to the development of new strategies to further enhance the therapeutic efficacy of oncolytic virotherapy.
2021-10-31 | GSE186753 | GEO
Project description:Although oncolytic adenoviruses have been widely studied for their direct oncolytic activity and immunomodulatory role in cancer immunotherapy, the immunosuppressive feedback loop induced by oncolytic adenoviruses remains poorly studied. Here, we showed that type V adenovirus (ADV) induces the polarization of tumor-associated macrophages (TAMs) to the M2 phenotype and increases the infiltration of regulatory T cells (Tregs) in the tumor microenvironment (TME). By selectively compensating for these deficiencies, Tα1 reprogrammed “M2-like” TAMs toward an antitumoral phenotype, thereby reprogramming the TME into a state more beneficial for antitumor immunity. Moreover, ADVTα1 was constructed by harnessing the merits of all the components for the aforementioned combinatorial therapy. Both in vitro and in vivo data showed that both exogenously supplied and adenovirus-produced Tα1 orchestrate TAM reprogramming and enhance the antitumor efficacy of ADV via CD8+ T cells, showing promising prospects for clinical translation. Our findings provide inspiration for improving oncolytic adenovirus combination therapy and designing new oncolytic engineered adenoviruses.
2024-07-04 | GSE271202 | GEO
Project description:Although oncolytic adenoviruses have been widely studied for their direct oncolytic activity and immunomodulatory role in cancer immunotherapy, the immunosuppressive feedback loop induced by oncolytic adenoviruses remains poorly studied. Here, we showed that type V adenovirus (ADV) induces the polarization of tumor-associated macrophages (TAMs) to the M2 phenotype and increases the infiltration of regulatory T cells (Tregs) in the tumor microenvironment (TME). By selectively compensating for these deficiencies, Tα1 reprogrammed “M2-like” TAMs toward an antitumoral phenotype, thereby reprogramming the TME into a state more beneficial for antitumor immunity. Moreover, ADVTα1 was constructed by harnessing the merits of all the components for the aforementioned combinatorial therapy. Both in vitro and in vivo data showed that both exogenously supplied and adenovirus-produced Tα1 orchestrate TAM reprogramming and enhance the antitumor efficacy of ADV via CD8+ T cells, showing promising prospects for clinical translation. Our findings provide inspiration for improving oncolytic adenovirus combination therapy and designing new oncolytic engineered adenoviruses.
2024-06-28 | GSE271046 | GEO
Project description:Oncolytic viruses are complex biological agents that interact at multiple levels with both tumor and normal tissues. Anti-viral pathways induced by interferon are known to play a critical role in determining tumor cell sensitivity and normal cell resistance to infection with oncolytic viruses. Here we pursue a synthetic biology approach to identify methods that enhance anti-tumor activity of oncolytic viruses through suppression of IFN signaling. Based on the mathematical analysis of multiple strategies, we hypothesize that a positive feedback loop, established by virus-mediated expression of a soluble interferon-binding decoy receptor, increases tumor cytotoxicity without compromising normal cells. Oncolytic rhabodviruses engineered to express a secreted interferon antagonist have improved oncolytic potential in cellular cancer models, and display improved therapeutic potential in tumor-bearing mice. Our results demonstrate the potential of this methodology in evaluating potential caveats of viral immune evasion strategies and improving the design of oncolytic viruses. The following series of microarray experiments was utilized to assess the impact of cloning an IFN decoy receptor isolated from vaccinia virus termed B19R on the transcriptional response against an IFN sensitive maraba virus strain termed MG1. RNA extraction was performed 24h post infection in 786-0 cells. Duplicate samples were pooled, and hybridized on Affymetrix human gene 1.0 ST arrays according to manufacturer instructions. Data analysis was performed using AltAnalyze. Briefly, probeset filtering implemented a DABG threshold of 70 & pV<0.05 and utilized exclusively constitutively expressed exons to assess levels of gene expression.
2013-06-01 | E-MTAB-1636 | biostudies-arrayexpress
Project description:The elucidation of therapy-induced changes to the class I major histocompatibility complex (MHC-I)-bound tumor antigens is crucial for understanding immune-mediated tumor eradication and identifying potential targets for peptide vaccines to enhance the efficacy of immunotherapies. Here, we investigated how oncolytic reovirus therapy with and without immune checkpoint blockade (ICB) alters the tumor peptide-MHC repertoire. Using mass spectrometry analysis of immunoaffinity purified MHC peptides, we first showed that changes to the MHC immunopeptidome following reovirus treatment is cancer type-dependent, where a murine fibrosarcoma model displayed quantitative and qualitative variance in differentially expressed peptides (DEPs) as compared to those identified in a murine ovarian cancer model. We then determined that the combination therapy of reovirus and ICB in the fibrosarcoma model resulted in higher numbers of DEPs relative to either monotherapy alone. Most importantly, we identified reovirus and ICB-induced MHC peptides that are biologically active in stimulating interferon-gamma response in cognate CD8+ T cells, which likely contribute to cancer immunoediting. These findings highlight the importance of therapy-induced changes to the MHC immunopeptidome in shaping the underlying anti-tumor immune responses during reovirus and ICB combination therapy.
2021-12-06 | PXD024369 | Pride
Project description:Tumor-specific T cells are crucial in anti-tumor immunity and act as targets for cancer immunotherapies. However, these cells are numerically scarce and functionally exhausted in tumor microenvironment (TME), leading to the inefficacious immunotherapies in most cancer patients. In contrast, emerging evidence suggested that tumor-irrelevant bystander T (TBYS) cells are abundant and preserve functional memory properties in TME. To leverage TBYS cells in TME to eradicate tumor cells, we developed an oncolytic virus-based immunotherapy that delivers TBYS cell epitopes (OV-BYTE) into tumor cells, which efficiently redirects the antigen specificity of tumor cells to preexisting TBYS cells and effectively retards tumor growth in multiple preclinical models. Remarkably, the OV-BYTE strategy curtailed tumor progression by targeting SARS-CoV-2-specific T cell memory induced by natural infection or vaccination, providing important insights into the improvement of cancer immunotherapies in a great population with a history of SARS-CoV-2 infection or COVID-19 vaccination.
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