Abstract Book 2010 - CIMT Annual Meeting

115 Lladser | Enhancing immunity & adjuvants
DAI (ZBP1/DLM-1) as a novel genetic adjuvant for cancer DNA
vaccines that promotes CTL responses, overcomes tolerance and
confers long-term tumor protection.
Alvaro Lladser 1 , Dimitrios Mougiakakos 1 , Helena Tufvesson 1 , Andrew F.G. Quest 2 , Karl
Ljungberg 1 *, Rolf Kiessling 1 *
1 Immune and Gene Therapy Laboratory, Cancer Center Karolinska, Department of Oncology and Pathology,
Karolinska Institutet. Karolinska Hospital R8:01, SE-17176 Stockholm, Sweden
2 Laboratory of Cellular Communication, FONDAP Center for Molecular Studies of the Cell, Program of Cellular
and Molecular Biology, Facultad de Medicina, Universidad de Chile, Santiago, Chile
* KL and RK contributed equally to this work
DNA vaccination is an attractive approach to induce
antigen-specific cytotoxic T cell (CTL) responses
capable of providing long-lasting protective immunity
against cancer. Although effective in animal
models, DNA vaccines against cancer have shown
limited efficacy in clinical trials. Therefore, efficient
delivery systems and powerful adjuvants are
needed for DNA vaccines to overcome tumor-associated
T cell tolerance. Indeed, the early activation
of innate immune receptors and downstream signaling
pathways are essential to promote effective
adaptive immunity. Consequently, DNA vaccines
benefit from adjuvants that boost innate immunity
signaling. We have used the recently described cytosolic
DNA sensor Z-DNA binding protein 1 (ZBP1
also known as DLM-1), termed DNA-dependent activator
of interferon regulatory factors (DAI) as a
genetic adjuvant for DNA vaccines. In vivo electroporation
(EP) of mice with a DAI-encoding plasmid
(pDAI) promoted transcription of genes encoding
type I interferons (IFNs), proinflammatory cytokines,
chemokines and co-stimulatory molecules.
Co-immunization of pDAI and antigen-encoding
plasmids enhanced both in vivo antigen-specific
proliferation and induction of CTLs. Moreover, codelivered
pDAI overcame CTL-tolerance to a tumorassociated
antigen (TAA) and conferred long-term
anti-tumor protection. The DAI-adjuvanted CTL induction
required NF-κB activation and intact type I
IFN signaling, but not interferon regulatory factor
(IRF) 3. This study demonstrates the potential of
using intracellular innate sensors as genetic adju-
vants to improve DNA vaccine potency.
Acknowledgements: Research described here has
been supported by grants to RK 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, “ALFProject” 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.
AL has been supported by a Fellowship for Postgraduate
Studies “Presidente de la República” from
CONICYT, Chile. DM was supported by a grant of
the German Research Association (DFG). KL has
been supported by a postdoctoral fellowship from
the Swedish Society for Medical Research.
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