Vaccines targeting self‐antigens: mechanisms and efficacy‐determining parameters

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 significandy aid the design of efficient, specific, and safe therapeutic cancer vaccines.—Saupe, F., Huijbers, E. J. M., Hein, T., Femel, J., Cedervall, J., Olsson, A.‐K., Hellman, L. Vaccines targeting self‐antigens: mechanisms and efficacy‐determining parameters. FASEB J. 29, 3253‐3262 (2015). www.fasebj.org