Harnessing DNA-induced immune responses for improving cancer vaccines

Herrada, Andrés A.; Rojas-Colonelli, Nicole; González-Figueroa, Paula; Roco, Jonathan A.; Oyarce, César; Ligtenberg, Maarten A.; Lladser, Álvaro

doi:10.4161/hv.22345

Cited by 31 publications

(23 citation statements)

References 141 publications

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“…After DNA vaccination, stroma cells at the injection site and DCs are directly transfected with the plasmid DNA construct (36). Then, the transfected cells transcribe and translate the encoded Ag, and it is subsequently presented to T cells directly by DCs or indirectly via stromal cells.…”

Section: Discussionmentioning

confidence: 99%

CD63-Mediated Antigen Delivery into Extracellular Vesicles via DNA Vaccination Results in Robust CD8+ T Cell Responses

Kanuma

Yamamoto

Kobiyama

et al. 2017

The Journal of Immunology

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DNA vaccines are attractive immunogens for priming humoral and cellular immune responses to the encoded Ag. However, their ability to induce Ag-specific CD8 T cell responses requires improvement. Among the strategies for improving DNA vaccine immunogenicity are booster vaccinations, alternate vaccine formulations, electroporation, and genetic adjuvants, but few, such as extracellular vesicles (EVs), target natural Ag delivery systems. By focusing on CD63, a tetraspanin protein expressed on various cellular membranes, including EVs, we examined whether a DNA vaccine encoding an Ag fused to CD63 delivered into EVs would improve vaccine immunogenicity. In vitro transfection with plasmid DNA encoding an OVA Ag fused to CD63 (pCD63-OVA) produced OVA-carrying EVs. Immunizations with the purified OVA-carrying EVs primed naive mice to induce OVA-specific CD4 and CD8 T cells, whereas immunization with EVs purified from cells transfected with control plasmids encoding OVA protein alone or a calnexin-OVA fusion protein delivered into the endoplasmic reticulum failed to do so. Vaccinating mice with pCD63-OVA induced potent Ag-specific T cell responses, particularly those from CD8 T cells. CD63 delivery into EVs led to better CD8 T cell responses than calnexin delivery into the endoplasmic reticulum. When we used a mouse tumor implantation model to evaluate pCD63-OVA as a therapeutic vaccine, the EV-delivered DNA vaccination significantly inhibited tumor growth compared with the control DNA vaccinations. These results indicate that EV Ag delivery via DNA vaccination offers a new strategy for eliciting strong CD8 T cell responses to the encoded Ag, making it a potentially useful cancer vaccine.

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Section: Discussionmentioning

confidence: 99%

CD63-Mediated Antigen Delivery into Extracellular Vesicles via DNA Vaccination Results in Robust CD8+ T Cell Responses

Kanuma

Yamamoto

Kobiyama

et al. 2017

The Journal of Immunology

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“…3B). Since DNA is a potent immunostimulator acting through several DNA-sensing receptors (31), this phenomenon may have potential therapeutic significance for the development of oncolytic parvoviruses (32).…”

Section: Discussionmentioning

confidence: 99%

The SAT Protein of Porcine Parvovirus Accelerates Viral Spreading through Induction of Irreversible Endoplasmic Reticulum Stress

Mészáros

Tóth

Olasz

et al. 2017

J Virol

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The SAT protein (SATp) of porcine parvovirus (PPV) accumulates in the endoplasmic reticulum (ER), and SAT deletion induces the slow-spreading phenotype. The in vitro comparison of the wild-type Kresse strain and its SAT knockout (SAT Ϫ ) mutant revealed that prolonged cell integrity and late viral release are responsible for the slower spreading of the SAT Ϫ virus. During PPV infection, regardless of the presence or absence of SATp, the expression of downstream ER stress response proteins (Xbp1 and CHOP) was induced. However, in the absence of SATp, significant differences in the quantity and the localization of CHOP were detected, suggesting a role of SATp in the induction of irreversible ER stress in infected cells. The involvement of the induction of irreversible ER stress in porcine testis (PT) cell necrosis and viral egress was confirmed by treatment of infected cells by ER stressinducing chemicals (MG132, dithiothreitol, and thapsigargin), which accelerated the egress and spreading of both the wild-type and the SAT Ϫ viruses. UV stress induction had no beneficial effect on PPV infection, underscoring the specificity of ER stress pathways in the process. However, induction of CHOP and its nuclear translocation cannot alone be responsible for the biological effect of SAT, since nuclear CHOP could not complement the lack of SAT in a coexpression experiment. IMPORTANCE SATp is encoded by an alternative open reading frame of the PPV genome. Earlier we showed that SATp of the attenuated PPV NADL-2 strain accumulates in the ER and accelerates virus release and spreading. Our present work revealed that slow spreading is a general feature of SAT Ϫ PPVs and is the consequence of prolonged cell integrity. PPV infection induced ER stress in infected cells regardless of the presence of SATp, as demonstrated by the morphological changes of the ER and expression of the stress response proteins Xbp1 and CHOP. However, the presence of SATp made the ER stress more severe and accelerated cell death during infection, as shown by the higher rate of expression of CHOP and alteration of the localization of CHOP. The beneficial effect of irreversible ER stress on PPV spread was confirmed by treatment of infected cells with ER stress-inducing chemicals.KEYWORDS CHOP, ER stress, SAT, Xbp1, alternative ORF, parvovirus, protoparvovirus, viral egress P orcine parvovirus (PPV) belongs to the species Ungulate protoparvovirus 1 in the genus Protoparvovirus. It is the causative agent of the stillbirth, mummification, embryonic death, infertility (SMEDI) syndrome in swine (1).A highly pathogenic strain with broad tissue tropism, strain Kresse, was isolated in the 1980s (2, 3). Kresse strain-infected piglets showed atypical signs of PPV infection, including necrotic lesions (4) on the lips, snout, tongue, and foot.The PPV single-stranded genome contains two major open reading frames (ORFs)

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“…A major goal of immunotherapy is to develop a specific immune response against tumor-associated antigens (TAAs), which are derived from proteins that are specifically or preferentially expressed in tumor cells in comparison to non-transformed healthy cells 1 . DNA vaccines represent a good strategy to prime T cell responses against TAAs 2 . Furthermore, DNA vaccines can be used to deliver one or more antigens in their native conformation to develop a broad immune response 2 .…”

Section: Introductionmentioning

confidence: 99%

Combination of immune checkpoint blockade with DNA cancer vaccine induces potent antitumor immunity against P815 mastocytoma

Lopes

Vanvarenberg

Kos

et al. 2018

Sci Rep

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DNA vaccination against cancer has become a promising strategy for inducing a specific and long-lasting antitumor immunity. However, DNA vaccines fail to generate potent immune responses when used as a single therapy. To enhance their activity into the tumor, a DNA vaccine against murine P815 mastocytoma was combined with antibodies directed against the immune checkpoints CTLA4 and PD1. The combination of these two strategies delayed tumor growth and enhanced specific antitumor immune cell infiltration in comparison to the corresponding single therapies. The combination also promoted IFNg, IL12 and granzyme B production in the tumor microenvironment and decreased the formation of liver metastasis in a very early phase of tumor development, enabling 90% survival. These results underline the complementarity of DNA vaccination and immune checkpoint blockers in inducing a potent immune response, by exploiting the generation of antigen-specific T cells by the vaccine and the ability of immune checkpoint blockers to enhance T cell activity and infiltration in the tumor. These findings suggest how and why a rational combination therapy can overcome the limits of DNA vaccination but could also allow responses to immune checkpoint blockers in a larger proportion of subjects.

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Harnessing DNA-induced immune responses for improving cancer vaccines

Cited by 31 publications

References 141 publications

CD63-Mediated Antigen Delivery into Extracellular Vesicles via DNA Vaccination Results in Robust CD8+ T Cell Responses

CD63-Mediated Antigen Delivery into Extracellular Vesicles via DNA Vaccination Results in Robust CD8+ T Cell Responses

The SAT Protein of Porcine Parvovirus Accelerates Viral Spreading through Induction of Irreversible Endoplasmic Reticulum Stress

Combination of immune checkpoint blockade with DNA cancer vaccine induces potent antitumor immunity against P815 mastocytoma

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