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

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.

• Authors: Laura Liebscher, Christine Weißenborn, Stefanie Langwisch, Björn-Oliver Gohlke, Robert Preissner, Gabriel A Rabinovich, Nina Christiansen, Holger Christiansen, Ana Claudia Zenclussen, Stefan Fest
• Journal: Cancer letters (Cancer Lett) Vol. 509 Pg. 105-114 (07 01 2021) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 33848518 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier B.V. All rights reserved.

Chemical References

• Cancer Vaccines
• Galectin 1
• Immunodominant Epitopes
• Lgals1 protein, mouse
• Vaccines, DNA

Topics

• Animals
• CD8-Positive T-Lymphocytes (drug effects, immunology)
• Cancer Vaccines (genetics, immunology, pharmacology)
• Cell Line, Tumor
• Cytotoxicity, Immunologic (drug effects)
• Epitope Mapping
• Female
• Galectin 1 (genetics, immunology)
• Immunodominant Epitopes
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology)
• Mice
• Neuroblastoma (drug therapy, genetics, immunology)
• Tumor Burden (drug effects)
• Tumor Escape (drug effects)
• Tumor Microenvironment
• Vaccination
• Vaccines, DNA (pharmacology)