Vaccination with ErbB-2 peptides prevents cancer stem cell expansion and suppresses the development of spontaneous tumors in MMTV-PyMT transgenic mice
- 859 Downloads
ErbB-2 has been implicated as a target for cancer-initiating cells in breast and other cancers. ErbB-2-directed peptide vaccines have been shown to be effective in prevention of spontaneous tumorigenesis of breast in neu transgenic mouse model, and cellular immunity is proposed as a mechanism for the anti-tumor efficacy. However, there has been no explanation as to how immunity suppresses tumorigenesis from the early stage carcinogenesis, when ErbB-2 expression in breast is low. Here, we investigated a peptide-based vaccine, which consists of two MHC class II epitopes derived from murine ErbB-2, to prevent the occurrence of spontaneous tumors in breast and assess immune impact on breast cancer stem cells. Female MMTV-PyMT transgenic mice were immunized with either ErbB-2 peptide vaccine, or a peptide from tetanus toxoid, or PBS in immune adjuvant. ErbB-2 peptides vaccine completely suppressed spontaneous breast tumors, and the efficacy was correlated with antigen-specific T-cell and antibody responses. In addition, immune serum from the mice of ErbB-2 vaccine group had an inhibitory effect on mammosphere-forming capacity and signaling through ErbB-2 and downstream Akt pathway in ErbB-2 overexpressing mouse mammary cancer cells. We provide evidence that multi-epitope class II peptides vaccine suppresses tumorigenesis of breast potentially by inhibiting the growth of cancer stem cells. We also suggest that a strategy of inducing strong immune responses using multi-epitope ErbB-2-directed helper vaccine might be useful in preventing breast cancer recurrence.
KeywordsBreast cancer ErbB-2 Peptide vaccine Cancer stem cell Spontaneous tumor
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (No. 2009-0068859). MLD is supported by the Athena Distinguished Professor of Breast Cancer Research.
Conflict of interest
The authors declare that they have no conflict of interest.
- 4.Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A 104(3):973–978. doi: 10.1073/pnas.0610117104 PubMedCentralCrossRefPubMedGoogle Scholar
- 7.Ahmed N, Salsman VS, Kew Y, Shaffer D, Powell S, Zhang YJ, Grossman RG, Heslop HE, Gottschalk S (2010) HER2-specific T cells target primary glioblastoma stem cells and induce regression of autologous experimental tumors. Clin Cancer Res 16(2):474–485. doi: 10.1158/1078-0432.CCR-09-1322 PubMedCentralCrossRefPubMedGoogle Scholar
- 8.Magnifico A, Albano L, Campaner S, Delia D, Castiglioni F, Gasparini P, Sozzi G, Fontanella E, Menard S, Tagliabue E (2009) Tumor-initiating cells of HER2-positive carcinoma cell lines express the highest oncoprotein levels and are sensitive to trastuzumab. Clin Cancer Res 15(6):2010–2021. doi: 10.1158/1078-0432.CCR-08-1327 CrossRefPubMedGoogle Scholar
- 10.Ithimakin S, Day KC, Malik F, Zen Q, Dawsey SJ, Bersano-Begey TF, Quraishi AA, Ignatoski KW, Daignault S, Davis A, Hall CL, Palanisamy N, Heath AN, Tawakkol N, Luther TK, Clouthier SG, Chadwick WA, Day ML, Kleer CG, Thomas DG, Hayes DF, Korkaya H, Wicha MS (2013) HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab. Cancer Res 73(5):1635–1646. doi: 10.1158/0008-5472.CAN-12-3349 PubMedCentralCrossRefPubMedGoogle Scholar
- 16.Disis ML, Gad E, Herendeen DR, Lai VP, Park KH, Cecil DL, O’Meara MM, Treuting PM, Lubet RA (2013) A multiantigen vaccine targeting neu, IGFBP-2, and IGF-IR prevents tumor progression in mice with preinvasive breast disease. Cancer Prev Res (Phila) 6(12):1273–1282. doi: 10.1158/1940-6207.CAPR-13-0182 CrossRefGoogle Scholar
- 18.Park KH, Gad E, Goodell V, Dang Y, Wild T, Higgins D, Fintak P, Childs J, Dela Rosa C, Disis ML (2008) Insulin-like growth factor-binding protein-2 is a target for the immunomodulation of breast cancer. Cancer Res 68(20):8400–8409. doi: 10.1158/0008-5472.CAN-07-5891 PubMedCentralCrossRefPubMedGoogle Scholar
- 19.Lin EY, Jones JG, Li P, Zhu L, Whitney KD, Muller WJ, Pollard JW (2003) Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 163(5):2113–2126. doi: 10.1016/S0002-9440(10)63568-7 PubMedCentralCrossRefPubMedGoogle Scholar
- 20.Rovero S, Amici A, Di Carlo E, Bei R, Nanni P, Quaglino E, Porcedda P, Boggio K, Smorlesi A, Lollini PL, Landuzzi L, Colombo MP, Giovarelli M, Musiani P, Forni G (2000) DNA vaccination against rat her-2/Neu p185 more effectively inhibits carcinogenesis than transplantable carcinomas in transgenic BALB/c mice. J Immunol 165(9):5133–5142CrossRefPubMedGoogle Scholar
- 21.Quaglino E, Iezzi M, Mastini C, Amici A, Pericle F, Di Carlo E, Pupa SM, De Giovanni C, Spadaro M, Curcio C, Lollini PL, Musiani P, Forni G, Cavallo F (2004) Electroporated DNA vaccine clears away multifocal mammary carcinomas in her-2/neu transgenic mice. Cancer Res 64(8):2858–2864CrossRefPubMedGoogle Scholar
- 24.Brown CE, Starr R, Martinez C, Aguilar B, D’Apuzzo M, Todorov I, Shih CC, Badie B, Hudecek M, Riddell SR, Jensen MC (2009) Recognition and killing of brain tumor stem-like initiating cells by CD8 + cytolytic T cells. Cancer Res 69(23):8886–8893. doi: 10.1158/0008-5472.CAN-09-2687 PubMedCentralCrossRefPubMedGoogle Scholar
- 25.Pellegatta S, Poliani PL, Corno D, Menghi F, Ghielmetti F, Suarez-Merino B, Caldera V, Nava S, Ravanini M, Facchetti F, Bruzzone MG, Finocchiaro G (2006) Neurospheres enriched in cancer stem-like cells are highly effective in eliciting a dendritic cell-mediated immune response against malignant gliomas. Cancer Res 66(21):10247–10252. doi: 10.1158/0008-5472.CAN-06-2048 CrossRefPubMedGoogle Scholar
- 27.Disis ML, Wallace DR, Gooley TA, Dang Y, Slota M, Lu H, Coveler AL, Childs JS, Higgins DM, Fintak PA, dela Rosa C, Tietje K, Link J, Waisman J, Salazar LG (2009) Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer. J Clin Oncol 27(28):4685–4692. doi: 10.1200/JCO.2008.20.6789 PubMedCentralCrossRefPubMedGoogle Scholar