Intravenous injection of oncolytic virus M1 awakes antitumor T cells and overcomes resistance to checkpoint blockade
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ABSTRACT:
PROVIDER: PRJNA639448 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR12014210.fastq.gz | Fastqsanger.gz | |||
| SRR12014211.fastq.gz | Fastqsanger.gz | |||
| SRR12014212.fastq.gz | Fastqsanger.gz | |||
| SRR12014213.fastq.gz | Fastqsanger.gz | |||
| SRR12014214.fastq.gz | Fastqsanger.gz |
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Project description:Reversing the highly immunosuppressive tumor microenvironment (TME) is essential to achieve long-term efficacy with cancer immunotherapy. Despite the impressive clinical response to checkpoint blockade in multiple types of cancer, only a minority of patients benefit from this approach. Here, we report that the oncolytic virus M1 induces immunogenic tumor cell death and subsequently restores the ability of dendritic cells to prime antitumor T cells. Intravenous injection of M1 disrupts immune tolerance in the privileged TME, reprogramming immune-silent (cold) tumors into immune-inflamed (hot) tumors. M1 elicits potent CD8+ T cell-dependent therapeutic effects and establishes long-term antitumor immune memory in poorly immunogenic tumor models. Pretreatment with M1 sensitizes refractory tumors to subsequent checkpoint blockade by boosting T-cell recruitment and upregulating the expression of PD-L1. These findings reveal the antitumor immunological mechanism of the M1 virus and indicated that oncolytic viruses are ideal cotreatments for checkpoint blockade immunotherapy.
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Project description:Although promising, dendritic cell (DC) vaccines still provide limited clinical benefits, mainly due to the immunosuppressive tumor microenvironment (TME) and the lack of tumor-associated antigens (TAAs). Oncolytic viruses are considered to be an ideal strategy to overcome immunosuppression and expose TAAs, therefore they may work synergistically with DC vaccines. In this study, we demonstrated that oncolytic virus M1 (OVM) can enhance the antitumor effects of DC vaccine in a variety of syngeneic tumor mouse models by increasing the infiltration of CD8+ effector T cells in the TME. Mechanically, we identified that tumor cells offset the function of DC vaccines through the myeloid immune checkpoint SIRPα-CD47, while OVM can downregulate the expression of SIRPα and CD47 in DCs and tumor cells, respectively. Based on the fact that OVM upregulates the expression of PD-L1 in DCs, PD-L1 blockade was introduced with the combination of DC vaccines and OVM, resulting in a further potentiation of antitumor activity. Overall, we revealed that OVM can strengthen the antitumor efficacy of DC vaccines by targeting the immune checkpoint SIRPα-CD47 axis, which exerts dominant immunosuppressive effects on DC vaccines.
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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:Previously we reported that a recombinant vaccinia virus (VACV) carrying a light-emitting fusion gene enters, replicates in, and reveals the locations of tumors in mice. A new recombinant VACV, GLV-1h68, as a simultaneous diagnostic and therapeutic agent, was constructed by inserting three expression cassettes (encoding Renilla luciferase-green fluorescent protein (RUC-GFP) fusion, b-galactosidase, and b-glucuronidase) into the F14.5L, J2R (encoding thymidine kinase, TK), and A56R (encoding hemagglutinin, HA) loci of the viral genome, respectively. Intravenous (i.v.) injections of GLV-1h68 (1 Ã 107 pfu/mouse) into nude mice with established (500 mm3) subcutaneous (s.c.) GI-101A human breast tumors were used to evaluate its toxicity, tumor targeting specificity and oncolytic efficacy. GLV-1h68 demonstrated an enhanced tumor targeting specificity and much reduced toxicity compared to its parental LIVP strains. The tumors colonized by GLV-1h68 exhibited growth, inhibition, and regression phases followed by tumor eradication within 130 days in 95% of the mice tested. Tumor regression in live animals was monitored in real time based on decreasing light emission, hence demonstrating the concept of a combined oncolytic virus-mediated tumor diagnosis and therapy system. Transcriptional profiling of regressing tumors based on a mouse-specific platform revealed gene expression signatures consistent with immune defense activation, inclusive of interferon stimulated genes (STAT-1 and IRF-7), cytokines, chemokines and innate immune effector function. These findings suggest that immune activation may combine with viral oncolysis to induce tumor eradication in this model, providing a novel perspective for the design of oncolytic viral therapies for human cancers. Objective: To determine the gene expression changes induced by GLV-1h68 vaccinia virus injection in mouse carrying human breast cancer implant and leading to tumor eradication. Methods: Gene expression was analyzed using oligonucleotide microarrays. Responsiveness to vaccina virus injection was assessed by toxicity and survival study, gene expression anaysis and tumor volume change. Result: The tumors colonized by GLV-1h68 exhibited growth, inhibition, and regression phases followed by tumor eradication within 130 days in 95% of the mice tested. Tumor regression in live animals was monitored in real time based on decreasing light emission, hence demonstrating the concept of a combined oncolytic virus-mediated tumor diagnosis and therapy system. Transcriptional profiling of regressing tumors based on a mouse-specific platform revealed gene expression signatures consistent with immune defense activation, inclusive of interferon stimulated genes (STAT-1 and IRF-7), cytokines, chemokines and innate immune effector function. Conclusion: Our findings suggest that immune activation may combine with viral oncolysis to induce tumor eradication in this model, providing a novel perspective for the design of oncolytic viral therapies for human cancers. Experiment Overall Design: tumor tissues 3 and 6 weeks post virus injection
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