Efficiency of G2/M-related tumor-associated antigen-targeting cancer immunotherapy depends on antigen expression in the cancer stem-like population.

Abstract

The aim of this study was to establish a novel efficient cancer DNA vaccine approach. Many tumor-associated antigens (TAAs) have been reported; however, there is little information of the efficiency of each TAA. Normal cells barely undergo mitosis, whereas cancer cells divide frequently and grow well. Thus, G2/M-related antigens are cancer cell-specific and are regarded to be suitable candidates as targets of cancer immunotherapy. In this study, we compared the efficiencies of G2/M-related antigens including Birc5, Aurka, Nke2 and Plk1 by using a DNA vaccination model. Mice that had been immunized with G2/M-related antigens coding plasmid were challenged with CT26 colon cancer cells. Interestingly, Birc5- and Aurka-immunized mice showed an anti-tumor effect, whereas Nek2- and Plk1-immunized mice did not show any anti-tumor effect. We investigated the expression of G2/M-related antigens in cancer stem-like cell (CSC)/cancer-initiating cell (CIC) population to verify the difference in the anti-tumor effect. CSCs/CICs were isolated as side population (SP) cells using Hoechst 33342 dye from CT 26 cells. It was found that Birc5 and Aurka are expressed in both CSCs/CICs and non-CSCs/CICs (shared antigens), whereas Nek2 and Plk1 are expressed preferentially in non-CSCs/CICs (non-CSC antigens). Therefore, antigen expression in the CSC/CIC population might be related to the anti-tumor efficiency of cancer immunotherapy. Furthermore, we established a heat shock protein (Hsp90)-fused Birc5 plasmid to improve anti-cancer immunity. Birc5 fused to the N-terminal region of Hsp90 showed a stronger anti-tumor effect, whereas Birc5 fused to the C-terminal region of Hsp90 did not show enhancement compared with Birc5. These observations indicate that expression in the CSC/CIC population is essential to achieve tumor regression and that fusing antigens to the N-terminal region of Hsp90 enhances the anti-tumor effect.

• Authors: Takashi Mori, Satoshi Nishizawa, Yoshihiko Hirohashi, Toshihiko Torigoe, Yasuaki Tamura, Akari Takahashi, Vitaly Kochin, Reona Fujii, Toru Kondo, Mark I Greene, Isao Hara, Noriyuki Sato
• Journal: Experimental and molecular pathology (Exp Mol Pathol) Vol. 92 Issue 1 Pg. 27-32 (Feb 2012) ISSN: 1096-0945 [Electronic] Netherlands
• PMID: 22001602 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 Elsevier Inc. All rights reserved.

Chemical References

• Antigens, Neoplasm
• Birc5 protein, mouse
• Cell Cycle Proteins
• HSP90 Heat-Shock Proteins
• Inhibitor of Apoptosis Proteins
• Proto-Oncogene Proteins
• Recombinant Fusion Proteins
• Repressor Proteins
• Survivin
• Vaccines, DNA
• AURKA protein, human
• Aurka protein, mouse
• Aurora Kinase A
• Aurora Kinases
• NIMA-Related Kinases
• Nek2 protein, mouse
• Protein Serine-Threonine Kinases
• polo-like kinase 1

Topics

• Animals
• Antigens, Neoplasm (immunology)
• Aurora Kinase A
• Aurora Kinases
• Cell Cycle Proteins (immunology)
• Cell Division (immunology)
• Cell Line, Tumor
• Colonic Neoplasms (pathology, therapy)
• Female
• G2 Phase (immunology)
• HSP90 Heat-Shock Proteins (immunology)
• Humans
• Inhibitor of Apoptosis Proteins (immunology)
• Mice
• Mice, Inbred BALB C
• NIMA-Related Kinases
• Neoplastic Stem Cells (immunology)
• Protein Serine-Threonine Kinases (immunology)
• Proto-Oncogene Proteins (immunology)
• Recombinant Fusion Proteins
• Repressor Proteins (immunology)
• Side-Population Cells
• Survivin
• Vaccination
• Vaccines, DNA