TY - JOUR
T1 - Vaccines targeting self-antigens
T2 - mechanisms and efficacy-determining parameters
AU - Saupe, Falk
AU - Huijbers, Elisabeth J M
AU - Hein, Tobias
AU - Femel, Julia
AU - Cedervall, Jessica
AU - Olsson, Anna-Karin
AU - Hellman, Lars
N1 - © FASEB.
PY - 2015/8
Y1 - 2015/8
N2 - We recently showed that it is possible to compromise tumor vessel function and, as a consequence, suppress growth of aggressive preclinical tumors by immunizing against the tumor vascular markers extra domain-A (ED-A) or -B (ED-B) of fibronectin, using a fusion protein consisting of the ED-A or ED-B peptide fused to bacterial thioredoxin. To address the mechanism behind fusion protein-induced immunization and the specific contribution of the different vaccine constituents to elicit an anti-self-antibody response, we immunized mice with modified or unmodified self-antigens, combined with different adjuvant components, and analyzed antibody responses by ELISA in sera. Several essential requirements to circumvent tolerance were identified: (1) a potent pattern recognition receptor agonist like an oligonucleotide containing unmethylated cytosine and guanine dinucleotides (CpG); (2) a depot adjuvant to keep the CpG at the site of injection; and (3) the presence of foreign sequences in the vaccine protein. Lack of either of these factors abolished the anti-self-response (P = 0.008). In mice genetically deficient for type I IFN signaling, there was a 60% reduction in the anti-self-response compared with wild-type (P = 0.011), demonstrating a key role of this pathway in CpG-induced circumvention of self-tolerance. Identification of these mechanistic requirements to generate a potent anti-self-immune response should significantly aid the design of efficient, specific, and safe therapeutic cancer vaccines.
AB - We recently showed that it is possible to compromise tumor vessel function and, as a consequence, suppress growth of aggressive preclinical tumors by immunizing against the tumor vascular markers extra domain-A (ED-A) or -B (ED-B) of fibronectin, using a fusion protein consisting of the ED-A or ED-B peptide fused to bacterial thioredoxin. To address the mechanism behind fusion protein-induced immunization and the specific contribution of the different vaccine constituents to elicit an anti-self-antibody response, we immunized mice with modified or unmodified self-antigens, combined with different adjuvant components, and analyzed antibody responses by ELISA in sera. Several essential requirements to circumvent tolerance were identified: (1) a potent pattern recognition receptor agonist like an oligonucleotide containing unmethylated cytosine and guanine dinucleotides (CpG); (2) a depot adjuvant to keep the CpG at the site of injection; and (3) the presence of foreign sequences in the vaccine protein. Lack of either of these factors abolished the anti-self-response (P = 0.008). In mice genetically deficient for type I IFN signaling, there was a 60% reduction in the anti-self-response compared with wild-type (P = 0.011), demonstrating a key role of this pathway in CpG-induced circumvention of self-tolerance. Identification of these mechanistic requirements to generate a potent anti-self-immune response should significantly aid the design of efficient, specific, and safe therapeutic cancer vaccines.
KW - Adjuvants, Immunologic/pharmacology
KW - Animals
KW - Antibody Formation/immunology
KW - Autoantigens/immunology
KW - Cancer Vaccines/immunology
KW - CpG Islands/immunology
KW - Female
KW - Fibronectins/immunology
KW - Immune Tolerance/immunology
KW - Interferon Type I/immunology
KW - Mice
KW - Mice, Inbred C57BL
KW - Neoplasms/immunology
U2 - 10.1096/fj.15-271502
DO - 10.1096/fj.15-271502
M3 - Article
C2 - 25868727
VL - 29
SP - 3253
EP - 3262
JO - FASEB Journal
JF - FASEB Journal
SN - 0892-6638
IS - 8
ER -