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01-05-2010 | Original Paper

Topoisomerase II alpha as a universal tumor antigen: antitumor immunity in murine tumor models and H-2K^b-restricted T cell epitope

Authors: Jung-Sun Park, Hye-Sung Kim, Mi-Young Park, Chang-Hyun Kim, Yeun-Jun Chung, Yong-Kil Hong, Tai-Gyu Kim

Published in: Cancer Immunology, Immunotherapy | Issue 5/2010

Abstract

Topoisomerase II alpha (Top2α) is an attractive candidate to be used as a tumor antigen for cancer immunotherapy, because it is abundantly expressed in various tumors and serves as a target for a number of chemotherapeutic agents. In this study, we demonstrated the immunogenicity of Top2α, using dendritic cells (DC) electroporated with RNA encoding the Top2α C-terminus (Top2αCRNA/DC). Top2αCRNA/DC were able to demonstrate in vitro stimulation of T cells from mice that were previously vaccinated with Top2α-expressing tumor lysate-pulsed DC. Vaccination with Top2αCRNA/DC induced Top2α-specific T cell responses in vivo as well as antitumor effects in various murine tumor models including MC-38, B16F10, and GL26. DC pulsed with p1327 (DSDEDFSGL), defined as an epitope presented by H-2K^b, also induced Top2α-specific immune responses and antitumor effects. Based on these data, Top2α is suggested to be a universal target for cancer immunotherapy.

Adachi N, Miyaike M, Kato S, Kanamaru R, Koyama H, Kikuchi A (1997) Cellular distribution of mammalian DNA topoisomerase II is determined by its catalytically dispensable C-terminal domain. Nucleic Acids Res 25:3135–3142CrossRefPubMed

Adachi N, Nomoto M, Kohno K, Koyama H (2000) Cell-cycle regulation of the DNA topoisomerase II alpha promoter is mediated by proximal CCAAT boxes: possible involvement of acetylation. Gene 245:49–57CrossRefPubMed

Al-Kuraya K, Novotny H, Bavi P, Siraj AK, Uddin S, Ezzat A, Sanea NA, Al-Dayel F, Al-Mana H, Sheikh SS, Mirlacher M, Tapia C, Simon R, Sauter G, Terracciano L, Tornillo L (2007) HER2, TOP2A, CCND1, EGFR and C-MYC oncogene amplification in colorectal cancer. J Clin Pathol 60:768–772CrossRefPubMed

Andersen MH, Pedersen LO, Becker JC, Straten PT (2001) Identification of a cytotoxic T lymphocyte response to the apoptosis inhibitor protein survivin in cancer patients. Cancer Res 61:869–872PubMed

Awwad M, North RJ (1990) Radiosensitive barrier to T-cell-mediated adoptive immunotherapy of established tumors. Cancer Res 50:2228–2233PubMed

Baumgaertner P, Rufer N, Devevre E, Derre L, Rimoldi D, Geldhof C, Voelter V, Lienard D, Romero P, Speiser DE (2006) Ex vivo detectable human CD8 T-cell responses to cancer-testis antigens. Cancer Res 66:1912–1916CrossRefPubMed

Boczkowski D, Nair SK, Snyder D, Gilboa E (1996) Dendritic cells pulsed with RNA are potent antigen-presenting cells in vitro and in vivo. J Exp Med 184:465–472CrossRefPubMed

Capranico G, Tinelli S, Austin CA, Fisher ML, Zunino F (1992) Different patterns of gene expression of topoisomerase II isoforms in differentiated tissues during murine development. Biochim Biophys Acta 1132:43–48PubMed

Choi BK, Kim YH, Kang WJ, Lee SK, Kim KH, Shin SM, Yokoyama WM, Kim TY, Kwon BS (2007) Mechanisms involved in synergistic anticancer immunity of anti-4-1BB and anti-CD4 therapy. Cancer Res 67:8891–8899CrossRefPubMed

10.

Gordan JD, Vonderheide RH (2002) Universal tumor antigens as targets for immunotherapy. Cytotherapy 4:317–327CrossRefPubMed

11.

Hande KR (1998) Clinical applications of anticancer drugs targeted to topoisomerase II. Biochim Biophys Acta 1400:173–184PubMed

12.

Inaba K, Inaba M, Romani N, Aya H, Deguchi M, Ikehara S, Muramatsu S, Steinman RM (1992) Generation of large numbers of dendritic cells from mouse bone marrow cultures supplemented with granulocyte/macrophage colony-stimulating factor. J Exp Med 176:1693–1702CrossRefPubMed

13.

Ito M, Shichijo S, Tsuda N, Ochi M, Harashima N, Saito N, Itoh K (2001) Molecular basis of T cell-mediated recognition of pancreatic cancer cells. Cancer Res 61:2038–2046PubMed

14.

Jenkins JR, Ayton P, Jones T, Davies SL, Simmons DL, Harris AL, Sheer D, Hickson ID (1992) Isolation of cDNA clones encoding the beta isozyme of human DNA topoisomerase II and localisation of the gene to chromosome 3p24. Nucleic Acids Res 20:5587–5592CrossRefPubMed

15.

Juenke JM, Holden JA (1993) The distribution of DNA topoisomerase II isoforms in differentiated adult mouse tissues. Biochim Biophys Acta 1216:191–196PubMed

16.

Kanta SY, Yamane T, Dobashi Y, Mitsui F, Kono K, Ooi A (2006) Topoisomerase II alpha gene amplification in gastric carcinomas: correlation with the HER2 gene. An immunohistochemical, immunoblotting, and multicolor fluorescence in situ hybridization study. Hum Pathol 37:1333–1343CrossRefPubMed

17.

Kosari F, Munz JM, Savci-Heijink CD, Spiro C, Klee EW, Kube DM, Tillmans L, Slezak J, Karnes RJ, Cheville JC, Vasmatzis G (2008) Identification of prognostic biomarkers for prostate cancer. Clin Cancer Res 14:1734–1743CrossRefPubMed

18.

Linka RM, Porter AC, Volkov A, Mielke C, Boege F, Christensen MO (2007) C-terminal regions of topoisomerase II alpha and II beta determine isoform-specific functioning of the enzymes in vivo. Nucleic Acids Res 35:3810–3822CrossRefPubMed

19.

Mano MS, Awada A, Di Leo A, Durbecq V, Paesmans M, Cardoso F, Larsimont D, Piccart M (2004) Rates of topoisomerase II-alpha and HER-2 gene amplification and expression in epithelial ovarian carcinoma. Gynecol Oncol 92:887–895CrossRefPubMed

20.

Muller MR, Grunebach F, Nencioni A, Brossart P (2003) Transfection of dendritic cells with RNA induces CD4- and CD8-mediated T cell immunity against breast carcinomas and reveals the immunodominance of presented T cell epitopes. J Immunol 170:5892–5896PubMed

21.

Nair SK, Boczkowski D, Morse M, Cumming RI, Lyerly HK, Gilboa E (1998) Induction of primary carcinoembryonic antigen (CEA)-specific cytotoxic T lymphocytes in vitro using human dendritic cells transfected with RNA. Nat Biotechnol 16:364–369CrossRefPubMed

22.

Nair SK, Heiser A, Boczkowski D, Majumdar A, Naoe M, Lebkowski JS, Vieweg J, Gilboa E (2000) Induction of cytotoxic T cell responses and tumor immunity against unrelated tumors using telomerase reverse transcriptase RNA transfected dendritic cells. Nat Med 6:1011–1017CrossRefPubMed

23.

Nakatsura T, Senju S, Ito M, Nishimura Y, Itoh K (2002) Cellular and humoral immune responses to a human pancreatic cancer antigen, coactosin-like protein, originally defined by the SEREX method. Eur J Immunol 32:826–836CrossRefPubMed

24.

Park MY, Kim HS, Woo SJ, Kim CH, Park JS, Sohn HJ, Kim HJ, Oh ST, Kim TG (2008) Efficient antitumor immunity in a murine colorectal cancer model induced by CEA RNA-electroporated B cells. Eur J Immunol 38:2106–2117CrossRefPubMed

25.

Rakhmilevich AL, North RJ (1994) Elimination of CD4⁺ T cells in mice bearing an advanced sarcoma augments the antitumor action of interleukin-2. Cancer Immunol Immunother 38:107–112PubMed

26.

Scanlan MJ, Simpson AJ, Old LJ (2004) The cancer/testis genes: review, standardization, and commentary. Cancer Immun 4:1PubMed

27.

Schoeffler AJ, Berger JM (2005) Recent advances in understanding structure-function relationships in the type II topoisomerase mechanism. Biochem Soc Trans 33:1465–1470CrossRefPubMed

28.

Schrader C, Meusers P, Brittinger G, Teymoortash A, Siebmann JU, Janssen D, Parwaresch R, Tiemann M (2004) Topoisomerase IIalpha expression in mantle cell lymphoma: a marker of cell proliferation and a prognostic factor for clinical outcome. Leukemia 18:1200–1206CrossRefPubMed

29.

Stone B, Schummer M, Paley PJ, Thompson L, Stewart J, Ford M, Crawford M, Urban N, O’Briant K, Nelson BH (2003) Serologic analysis of ovarian tumor antigens reveals a bias toward antigens encoded on 17q. Int J Cancer 104:73–84CrossRefPubMed

30.

Van Tendeloo VF, Ponsaerts P, Lardon F, Nijs G, Lenjou M, Van Broeckhoven C, Van Bockstaele DR, Berneman ZN (2001) Highly efficient gene delivery by mRNA electroporation in human hematopoietic cells: superiority to lipofection and passive pulsing of mRNA and to electroporation of plasmid cDNA for tumor antigen loading of dendritic cells. Blood 98:49–56CrossRefPubMed

31.

Vonderheide RH (2002) Telomerase as a universal tumor-associated antigen for cancer immunotherapy. Oncogene 21:674–679CrossRefPubMed

32.

Willman JH, Holden JA (2000) Immunohistochemical staining for DNA topoisomerase II-alpha in benign, premalignant, and malignant lesions of the prostate. Prostate 42:280–286CrossRefPubMed

33.

Woessner RD, Mattern MR, Mirabelli CK, Johnson RK, Drake FH (1991) Proliferation- and cell cycle-dependent differences in expression of the 170 kilodalton and 180 kilodalton forms of topoisomerase II in NIH-3T3 cells. Cell Growth Differ 2:209–214PubMed

34.

Wong N, Yeo W, Wong WL, Wong NL, Chan KY, Mo FK, Koh J, Chan SL, Chan AT, Lai PB, Ching AK, Tong JH, Ng HK, Johnson PJ, To KF (2009) TOP2A overexpression in hepatocellular carcinoma correlates with early age onset, shorter patients survival and chemoresistance. Int J Cancer 124:644–652CrossRefPubMed

35.

Zhao H, Yu H, Liu Y, Wang Y, Cai W (2008) DNA topoisomerase II-alpha as a proliferation marker in human gliomas: correlation with PCNA expression and patient survival. Clin Neuropathol 27:83–90PubMed

Title: Topoisomerase II alpha as a universal tumor antigen: antitumor immunity in murine tumor models and H-2Kb-restricted T cell epitope
Authors: Jung-Sun Park
Hye-Sung Kim
Mi-Young Park
Chang-Hyun Kim
Yeun-Jun Chung
Yong-Kil Hong
Tai-Gyu Kim
Publication date: 01-05-2010
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 5/2010
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-009-0795-3

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