title: 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: Department of Pathology, Sapporo Medical University, School of Medicine, South-1 West-17, Chuo-Ku, Sapporo 060-8556, Japan.
authors: Takashi
authors: T
authors: Mori
authors: Satoshi
authors: S
authors: Nishizawa
authors: Yoshihiko
authors: Y
authors: Hirohashi
authors: Toshihiko
authors: T
authors: Torigoe
authors: Yasuaki
authors: Y
authors: Tamura
authors: Akari
authors: A
authors: Takahashi
authors: Vitaly
authors: V
authors: Kochin
authors: Reona
authors: R
authors: Fujii
authors: Toru
authors: T
authors: Kondo
authors: Mark I
authors: MI
authors: Greene
authors: Isao
authors: I
authors: Hara
authors: Noriyuki
authors: N
authors: Sato
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D064096:Aurora Kinase A; D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology / Q000628:therapy; D005260:Female; D016195:G2 Phase / Q000276:immunology; D018841:HSP90 Heat-Shock Proteins / Q000276:immunology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D000072379:NIMA-Related Kinases; D014411:Neoplastic Stem Cells / Q000276:immunology*; D017346:Protein Serine-Threonine Kinases / Q000276:immunology*; D011518:Proto-Oncogene Proteins / Q000276:immunology; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins / Q000276:immunology*; D058985:Side-Population Cells; D000077022:Survivin; D014611:Vaccination; D019444:Vaccines, DNA; D000097869:Polo-Like Kinase 1
chemical_list: D000951:Antigens, Neoplasm; D064096:Aurora Kinase A; D064127:Aurora Kinases; D018797:Cell Cycle Proteins; D018841:HSP90 Heat-Shock Proteins; D051034:Inhibitor of Apoptosis Proteins; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000077022:Survivin; D019444:Vaccines, DNA; D000097869:Polo-Like Kinase 1; C117749:Birc5 protein, mouse; C576917:AURKA protein, human; C576918:Aurka protein, mouse; C490317:Nek2 protein, mouse