Efficient Induction of Cytotoxic T Cells by Viral Vector Vaccination Requires STING-Dependent DC Functions

Barnowski, Cornelia; Ciupka, Gregor; Tao, Ronny; Jin, Lei; Busch, Dirk H.; Tao, Sha; Drexler, Ingo

doi:10.3389/fimmu.2020.01458

Cited by 13 publications

(15 citation statements)

References 89 publications

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“…As poxviruses replicate their DNA genomes in the cytoplasm, they must avoid detection by a number of DNA sensors. It has been demonstrated that MVA triggers an antiviral response in several human and mouse cell types in a cGAS-and STING-dependent manner [32][33][34][35]. This is in agreement with the absence of multiple viral immunomodulators in the virus as a result of multiple genomic alterations that occurred during its extensive passage in avian cells.…”

Section: Discussionsupporting

confidence: 67%

“…Poxin is highly conserved in orthopoxviruses (OPXV) but it is inactivated in MVA [29,30]. Whilst viruses carrying poxin effectively prevent STING activation, MVA infection of human and mouse cells results in strong induction of IFN and pro-inflammatory cytokines that is dependent on cGAS and STING [31][32][33] that is crucial for the establishment of cytotoxic T cell responses and memory T cell formation [34,35]. The cGAS/STING axis is therefore essential for the antiviral response against MVA.…”

Section: Introductionmentioning

confidence: 99%

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Disruption of the cGAS/STING axis does not impair sensing of MVA in BHK21 cells

Hood

Sumner

Motes

2022

Journal of General Virology

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Modified vaccinia Ankara (MVA) is an attenuated strain of vaccinia virus (VACV), a dsDNA virus that replicates its genome in the cytoplasm and as a result is canonically sensed by the cyclic GMP-AMP synthase (cGAS) and its downstream stimulator of interferon genes (STING). MVA has a highly restricted host range due to major deletions in its genome including inactivation of immunomodulatory genes, only being able to grow in avian cells and the hamster cell line BHK21. Here we studied the interplay between MVA and the cGAS/STING DNA in this permissive cell line and determined whether manipulation of this axis could impact MVA replication and cell responses. We demonstrate that BHK21 cells retain a functional cGAS/STING axis that responds to canonical DNA sensing agonists, upregulating interferon stimulated genes (ISGs). BHK21 cells also respond to MVA, but with a distinct ISG profile. This profile remains unaltered after CRISPR/Cas9 knock-out editing of STING and ablation of cytosolic DNA responses, indicating that MVA responses are independent of the cGAS/STING axis. Furthermore, infection by MVA diminishes the ability of BHK21 cells to respond to exogenous DNA suggesting that MVA still encodes uncharacterised inhibitors of DNA sensing. This suggests that using attenuated strains in permissive cell lines may assist in identification of novel host-virus interactions that may be of relevance to disease or the therapeutic applications of poxviruses.

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Section: Discussionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Disruption of the cGAS/STING axis does not impair sensing of MVA in BHK21 cells

Hood

Sumner

Motes

2022

Journal of General Virology

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“…Consistent with this, we now find that heat-iMVA infection of BMDCs promotes antigen cross-presentation, which requires STING. Barnowski et al 57 showed that the STING pathway contributes to the generation of VACV immunodominant B8-specific CD8 + T cell, but not to anti-OVA CD8 + T cell responses, after intraperitoneal vaccination with MVA expressing OVA. Together, these results show that the STING pathway is involved in MVA-induced antiviral adaptive immunity as well as the MVA-mediated adjuvant effect.…”

Section: Discussionmentioning

confidence: 99%

Heat-inactivated modified vaccinia virus Ankara boosts Th1 cellular and humoral immunity as a vaccine adjuvant

et al. 2022

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Protein or peptide-based subunit vaccines have generated excitement and renewed interest in combating human cancer or COVID-19 outbreak. One major concern for subunit vaccine application is the weak immune responses induced by protein or peptides. Developing novel and effective vaccine adjuvants are critical for the success of subunit vaccines. Here we explored the potential of heat-inactivated MVA (heat-iMVA) as a vaccine adjuvant. Heat-iMVA dramatically enhances T cell responses and antibodies responses, mainly toward Th1 immune responses when combined with protein or peptide-based immunogen. The adjuvant effect of Heat-iMVA is stronger than live MVA and is dependent on the cGAS/STING-mediated cytosolic DNA-sensing pathway. In a therapeutic vaccination model based on tumor neoantigen peptide vaccine, Heat-iMVA significantly extended the survival and delayed tumor growth. When combined with SARS-CoV-2 spike protein, Heat-iMVA induced more robust spike-specific antibody production and more potent neutralization antibodies. Our results support that Heat-iMVA can be developed as a safe and potent vaccine adjuvant for subunit vaccines against cancer or SARS-CoV-2.

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“…Consistent with this, we now find that heat-iMVA infection of BMDCs promotes antigen cross-presentation, which requires STING. Barnowski et al showed that the STING pathway contributes to the generation of vaccinia immunodominant B8-specific CD8 + T cell, but not to anti-OVA CD8 + T cell responses, after intraperitoneal vaccination with MVA expressing OVA 47 . Together, these results show that the STING pathway is involved in poxvirus-induced antiviral adaptive immunity as well as the poxvirus-mediated adjuvant effect.…”

Section: Discussionmentioning

confidence: 99%

Heat-inactivated modified vaccinia virus Ankara boosts Th1-biased cellular and humoral immune responses as a vaccine adjuvant by activating the STING-mediated cytosolic DNA-sensing pathway

Yang

Garzia

Meyer

et al. 2021

Preprint

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Background: Protein or peptide-based subunit vaccines are promising platforms for combating human cancers and infectious diseases. However, one primary concern regarding subunit vaccines is the relatively weak immune responses induced by proteins or peptides. Therefore, developing novel and effective vaccine adjuvants is critical for the success of subunit vaccines. Modified vaccinia virus (MVA) is a safe and effective vaccine against smallpox and monkeypox. In this study, we explored the potential of heat-inactivated MVA (heat-iMVA) as a novel vaccine adjuvant. Methods: We co-administered heat-iMVA with a model antigen, chicken ovalbumin (OVA), either intramuscularly or subcutaneously twice, two weeks apart, and analyzed anti-OVA specific CD8+ and CD4+ T cells in the spleens and skin draining lymph nodes (dLNs) and serum anti-OVA IgG1 and IgG2c antibodies. We also compared the adjuvant effects of heat-iMVA with several known vaccine adjuvants. In addition, we tested whether co-administration of heat-iMVA plus tumor neoantigen peptides or irradiated tumor cells improves antitumor efficacy in a B16-F10 murine melanoma therapeutic vaccination model. Using Stimulator of Interferon Genes (STING) or Batf3-deficient mice, we evaluated the contribution of the STING pathway and Batf3-dependent CD103+/CD8alpha DCs in heat-iMVA-induced immunity. Results: Co-administration of protein- or peptide-based immunogens with heat-iMVA dramatically enhances Th1-biased cellular and humoral immune responses. This adjuvant effect of heat-iMVA is dependent on the STING-mediated cytosolic DNA-sensing pathway, and the antigen-specific CD8+ T cell response requires Batf3-dependent CD103+/CD8alpha dendritic cells (DCs). Heat-iMVA infection of bone marrow-derived DCs (BMDCs) promoted antigen cross-presentation, whereas live MVA infection did not. RNA-seq analyses revealed that heat-iMVA is a more potent activator of the STING pathway than live MVA. Additionally, combining tumor neoantigen peptides or irradiated tumor cells with heat-iMVA delayed tumor growth and extended the median survival in B16-F10 therapeutic vaccination models. Conclusions: Heat-iMVA induces type I interferon (IFN) production and antigen cross-presentation via a STING-dependent mechanism in DCs. Co-administration of heat-iMVA with peptide antigen generates strong Th1-biased cellular and humoral immunity. Collectively, our results demonstrate that heat-iMVA is a safe and potent vaccine adjuvant.

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Efficient Induction of Cytotoxic T Cells by Viral Vector Vaccination Requires STING-Dependent DC Functions

Cited by 13 publications

References 89 publications

Disruption of the cGAS/STING axis does not impair sensing of MVA in BHK21 cells

Disruption of the cGAS/STING axis does not impair sensing of MVA in BHK21 cells

Heat-inactivated modified vaccinia virus Ankara boosts Th1 cellular and humoral immunity as a vaccine adjuvant

Heat-inactivated modified vaccinia virus Ankara boosts Th1-biased cellular and humoral immune responses as a vaccine adjuvant by activating the STING-mediated cytosolic DNA-sensing pathway

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