A minigene DNA vaccine encoding peptide epitopes derived from Galectin-1 has protective antitumoral effects in a model of neuroblastoma. (1st July 2021)

• Record Type: Journal Article
• Authors: Liebscher, Laura; Weißenborn, Christine; Langwisch, Stefanie; Gohlke, Björn-Oliver; Preissner, Robert; Rabinovich, Gabriel A.; Christiansen, Nina; Christiansen, Holger; Zenclussen, Ana Claudia; Fest, Stefan
• Is Part Of: Cancer letters. Volume 509(2021)
• Page Start: 105
• Page End: 114
• Publication Date: 2021-07-01
• Subjects: Galectin-1 -- Neuroblastoma -- DNA vaccine -- Salmonella typhimurium -- Immunotherapy; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2021.03.020
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: We recently identified Galectin-1 (Gal-1), a β-galactoside-binding lectin, as a novel immune regulator in neuroblastoma (NB). Here, we characterized the tolerogenic function of Gal-1 within the CD8 + T cell compartment and further evaluated its relevance as an antigen for effective DNA vaccination against NB in a mouse model. NB cells with Gal-1 knockdown (NXS-2L) exhibited significantly reduced tumor growth compared to NXS-2 NB cells. Administration of anti-CD8 antibodies prevented this antitumor effect, with primary tumor growth comparable to that from Gal-1 (G1)-sufficient NB cells. Peptide epitope screening with online databases and in silico docking experiments predicted the sequences "FDQADLTI" (#1), "GDFKIKCV" (#2), and "AHGDANTI" (#3) to have superior H2-KK binding affinities and "KFPNRLNM" (#4), "DGDFKIKCV" (#5), and "LGKDSNNL" (#6) to have superior H2-DD binding affinities. Minigenes encoding G1-KK (#1-#2-#3), G1-DD (#4-#5-#6) and the triplet with the highest affinity, G1-H (#1-#2-#4), were generated and cloned into a ubiquitin-containing plasmid (pU). Mice receiving pU-G1-KK or pU-G-1H presented a reduction in the s.c. tumor volume and weight of up to 80% compared to control mice; this reduction was associated with increased cytotoxicity of isolated splenocytes from vaccinated animals. Vaccination with pUG1-DD showed a lower capability to suppress primary tumor progression. In conclusion, Gal-1 expression by NB negatively regulates CD8 + T cells. Vaccination with DNA plasmids encoding Gal-1 epitopes overcomes immune escape, enhances CD8 + T cell-dependent immunity and displays effective antitumor activity against NB. Highlights: Depletion of CD8 T cells induces rapid tumor growth in mice bearing Galectin-1-silenced neuroblastoma. Galectin-1 DNA minigene vaccines encode for peptide epitopes with high binding affinities to MHC class I molecules. Galectin-1 DNA vaccination suppresses neuroblastoma tumor growth and dissemination in immunocompetent mice.