DAI (DLM-1/ZBP1) as a genetic adjuvant for DNA vaccines that promotes effective antitumor CTL immunity

Alvaro Lladser; Dimitrios Mougiakakos; Helena Tufvesson; Maarten A. Ligtenberg; Andrew F.G. Quest; Rolf Kiessling; Karl Ljungberg

doi:10.1038/mt.2010.268

DAI (DLM-1/ZBP1) as a genetic adjuvant for DNA vaccines that promotes effective antitumor CTL immunity

Alvaro Lladser^*, Dimitrios Mougiakakos, Helena Tufvesson, Maarten A. Ligtenberg, Andrew F.G. Quest, Rolf Kiessling, Karl Ljungberg

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

48 Scopus citations

Abstract

DNA vaccination is an attractive approach to induce antigen-specific cytotoxic CD8⁺ T lymphocytes (CTLs), which can mediate protective antitumor immunity. The potency of DNA vaccines encoding weakly immunogenic tumor-associated antigens (TAAs) can be enhanced by codelivering gene-encoded adjuvants. Pattern recognition receptors (PRRs) that sense intracellular DNA could potentially be used to harness intrinsic immune-stimulating properties of plasmid DNA vaccines. Consequently, the cytosolic DNA sensor, DNA-dependent activator of interferon (IFN) regulatory factors (DAI), was used as a genetic adjuvant. In vivo electroporation (EP) of mice with a DAI-encoding plasmid (pDAI) promoted transcription of genes encoding type I IFNs, proinflammatory cytokines, and costimulatory molecules. Coimmunization with pDAI and antigen-encoding plasmids enhanced in vivo antigen-specific proliferation, and induction of effector and memory CTLs. Moreover, codelivery of pDAI effectively promoted CTL and CD4⁺ Th1 responses to the TAA survivin. The DAI-enhanced CTL induction required nuclear factor B (NF-B) activation and type I IFN signaling, but did not involve the IFN regulatory factor 3 (IRF3). Codelivery of pDAI also increased CTL responses to the melanoma-associated antigen tyrosinase-related protein-2 (TRP2), enhanced tumor rejection and conferred long-term protection against B16 melanoma challenge. This study constitutes proof-of-principle validating the use of intracellular PRRs as genetic adjuvants to enhance DNA vaccine potency.

Original language	English
Pages (from-to)	594-601
Number of pages	8
Journal	Molecular Therapy
Volume	19
Issue number	3
DOIs	https://doi.org/10.1038/mt.2010.268
State	Published - 2011
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by grants to R.K. from the Swedish Cancer Society, the Swedish Medical Research Council, the Cancer Society of Stockholm, the European Union (Grant “EUCAAD” and “DC-THERA”), the Karolinska Institutet, “ALF-Project” grants from the Stockholm City Council. AFGQ has received support from ICGEB (International Center of Genetic Engineering and Biotechnology, Trieste, Italy) grant CRP/CH102-01, Wellcome Trust award WT06491I/Z/01/Z and FONDAP grant 15010006. A.L. has been supported by a Fellowship for Postgraduate Studies “Presidente de la República” from CONICYT, Chile. D.M. was supported by a grant of the German Research Association (DFG). K.L. has been supported by a postdoctoral fellowship from the Swedish Society for Medical Research.

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics
Pharmacology
Drug Discovery

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/mt.2010.268

Cite this

@article{ffe887b916254d379889f336607acb08,

title = "DAI (DLM-1/ZBP1) as a genetic adjuvant for DNA vaccines that promotes effective antitumor CTL immunity",

abstract = "DNA vaccination is an attractive approach to induce antigen-specific cytotoxic CD8+ T lymphocytes (CTLs), which can mediate protective antitumor immunity. The potency of DNA vaccines encoding weakly immunogenic tumor-associated antigens (TAAs) can be enhanced by codelivering gene-encoded adjuvants. Pattern recognition receptors (PRRs) that sense intracellular DNA could potentially be used to harness intrinsic immune-stimulating properties of plasmid DNA vaccines. Consequently, the cytosolic DNA sensor, DNA-dependent activator of interferon (IFN) regulatory factors (DAI), was used as a genetic adjuvant. In vivo electroporation (EP) of mice with a DAI-encoding plasmid (pDAI) promoted transcription of genes encoding type I IFNs, proinflammatory cytokines, and costimulatory molecules. Coimmunization with pDAI and antigen-encoding plasmids enhanced in vivo antigen-specific proliferation, and induction of effector and memory CTLs. Moreover, codelivery of pDAI effectively promoted CTL and CD4+ Th1 responses to the TAA survivin. The DAI-enhanced CTL induction required nuclear factor B (NF-B) activation and type I IFN signaling, but did not involve the IFN regulatory factor 3 (IRF3). Codelivery of pDAI also increased CTL responses to the melanoma-associated antigen tyrosinase-related protein-2 (TRP2), enhanced tumor rejection and conferred long-term protection against B16 melanoma challenge. This study constitutes proof-of-principle validating the use of intracellular PRRs as genetic adjuvants to enhance DNA vaccine potency.",

author = "Alvaro Lladser and Dimitrios Mougiakakos and Helena Tufvesson and Ligtenberg, {Maarten A.} and Quest, {Andrew F.G.} and Rolf Kiessling and Karl Ljungberg",

note = "Funding Information: This work was supported by grants to R.K. from the Swedish Cancer Society, the Swedish Medical Research Council, the Cancer Society of Stockholm, the European Union (Grant “EUCAAD” and “DC-THERA”), the Karolinska Institutet, “ALF-Project” grants from the Stockholm City Council. AFGQ has received support from ICGEB (International Center of Genetic Engineering and Biotechnology, Trieste, Italy) grant CRP/CH102-01, Wellcome Trust award WT06491I/Z/01/Z and FONDAP grant 15010006. A.L. has been supported by a Fellowship for Postgraduate Studies “Presidente de la Rep{\'u}blica” from CONICYT, Chile. D.M. was supported by a grant of the German Research Association (DFG). K.L. has been supported by a postdoctoral fellowship from the Swedish Society for Medical Research.",

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month = mar,

doi = "10.1038/mt.2010.268",

language = "English",

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AU - Lladser, Alvaro

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AU - Ligtenberg, Maarten A.

AU - Quest, Andrew F.G.

AU - Kiessling, Rolf

AU - Ljungberg, Karl

N1 - Funding Information: This work was supported by grants to R.K. from the Swedish Cancer Society, the Swedish Medical Research Council, the Cancer Society of Stockholm, the European Union (Grant “EUCAAD” and “DC-THERA”), the Karolinska Institutet, “ALF-Project” grants from the Stockholm City Council. AFGQ has received support from ICGEB (International Center of Genetic Engineering and Biotechnology, Trieste, Italy) grant CRP/CH102-01, Wellcome Trust award WT06491I/Z/01/Z and FONDAP grant 15010006. A.L. has been supported by a Fellowship for Postgraduate Studies “Presidente de la República” from CONICYT, Chile. D.M. was supported by a grant of the German Research Association (DFG). K.L. has been supported by a postdoctoral fellowship from the Swedish Society for Medical Research.

PY - 2011/3

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N2 - DNA vaccination is an attractive approach to induce antigen-specific cytotoxic CD8+ T lymphocytes (CTLs), which can mediate protective antitumor immunity. The potency of DNA vaccines encoding weakly immunogenic tumor-associated antigens (TAAs) can be enhanced by codelivering gene-encoded adjuvants. Pattern recognition receptors (PRRs) that sense intracellular DNA could potentially be used to harness intrinsic immune-stimulating properties of plasmid DNA vaccines. Consequently, the cytosolic DNA sensor, DNA-dependent activator of interferon (IFN) regulatory factors (DAI), was used as a genetic adjuvant. In vivo electroporation (EP) of mice with a DAI-encoding plasmid (pDAI) promoted transcription of genes encoding type I IFNs, proinflammatory cytokines, and costimulatory molecules. Coimmunization with pDAI and antigen-encoding plasmids enhanced in vivo antigen-specific proliferation, and induction of effector and memory CTLs. Moreover, codelivery of pDAI effectively promoted CTL and CD4+ Th1 responses to the TAA survivin. The DAI-enhanced CTL induction required nuclear factor B (NF-B) activation and type I IFN signaling, but did not involve the IFN regulatory factor 3 (IRF3). Codelivery of pDAI also increased CTL responses to the melanoma-associated antigen tyrosinase-related protein-2 (TRP2), enhanced tumor rejection and conferred long-term protection against B16 melanoma challenge. This study constitutes proof-of-principle validating the use of intracellular PRRs as genetic adjuvants to enhance DNA vaccine potency.

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DAI (DLM-1/ZBP1) as a genetic adjuvant for DNA vaccines that promotes effective antitumor CTL immunity

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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