Abstract
Heparanase is expressed in almost all advanced tumors, and therefore it may serve as a potential target for tumor therapy. Our previous study has shown that heparanase can serve as a potential universal tumor-associated antigen (TAA) for the immunotherapy of advanced tumors. Further study demonstrated that the HLA-A*0201-restricted Cytotoxic T lymphocytes (CTL) epitopes Hpa525 (PAFSYSFFV), Hpa277 (KMLKSFLKA) and Hpa405 (WLSLLFKKL) from human heparanase could induce a potent anti-tumor immune response in vitro. The present study was designed to investigate whether the above peptides could induce immune responses in mice. Our results demonstrated that the effectors from heparanase peptide-immunized mice could effectively lyse various tumor cells that were heparanase positive and HLA-A*0201 matched. We also found that these peptide-specific CTLs did not lyse autologous lymphocytes that had low heparanase activity. Further study revealed that Hpa525, Hpa277, and Hpa405 peptides increased the frequency of IFN-γ-producing T cells as compared to a negative peptide. These results suggest that Hpa525, Hpa277, and Hpa405 peptides are novel HLA-A*0201-restricted CTL epitopes capable of inducing heparanase-specific CTLs in mice. Because heparanase is expressed in most advanced malignant tumors, Hpa525, Hpa277, and Hpa405 peptide-based vaccines may be useful for the immunotherapy of patients with advanced tumors.
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Abbreviations
- Hpa:
-
Heparanase
- TAA:
-
Tumor-associated antigen
- DC:
-
Dendritic cell
- CTLs:
-
Cytotoxic T lymphocytes
- E/T:
-
Effector-to-target
References
Joyce JA, Freeman C, Meyer-Morse N, Parish CR, Hanahan D (2005) A functional heparan sulfate mimetic implicates both heparanase and heparan sulfate in tumor angiogenesis and invasion in a mouse model of multistage cancer. Oncogene 24(25):4037–4051
Vlodavsky I, Goldshmidt O, Zcharia E, Atzmon R, Rangini-Guatta Z, Elkin M, Peretz T, Friedmann Y (2002) Mammalian heparanase: involvement in cancer metastasis, angiogenesis and normal development. Semin Cancer Biol 12(2):121–129
Beckhove P, Helmke BM, Ziouta Y, Bucur M, Dörner W, Mogler C, Dyckhoff G, Herold-Mende C (2005) Heparanase expression at the invasion front of human head and neck cancers and correlation with poor prognosis. Clin Cancer Res 11(8):2899–2906
Bercovici N, Haicheur N, Massicard S, Vernel-Pauillac F (2008) Analysis and characterization of antitumor T-cell response after administration of dendritic cells loaded with allogeneic tumor lysate to metastatic melanoma patients. J Immunother 31(1):101–112
Zhu B, Chen Z, Cheng X, Lin Z, Guo J, Jia Z, Zou L, Wang Z, Hu Y, Wang D, Wu Y (2003) Identification of HLA-A*0201-restricted cytotoxic T lymphocyte epitope from TRAG-3 antigen. Clin Cancer Res 9(5):1850–1857
Harada M, Li YF, El-Gamil M, Rosenberg SA, Robbins PF (2001) Use of an in vitro immunoselected tumor line to identify shared melanoma antigens recognized by HLA-A*0201-restricted T cells. Cancer Res 61(3):1089–1094
Zinkernagel RM, Doherty PC (1997) The discovery of MHC restriction. Immunol Today 18(1):14–17
York IA, Rock KL (1996) Antigen processing and presentation by the class I major histocompatibility complex. Annu Rev Immunol 14(1):369–396
Rammensee HG, Falk K, Rotzschke O (1993) Peptides naturally presented by MHC class I molecules. Annu Rev Immunol 11(1):213–244
Tuting T, Steitz J, Bruck J et al (1999) Dendritic cell-based genetic immunization in mice with a recombinant adenovirus encoding murine TRP2 induces effective anti-melanoma immunity. J Gene Med 1(1):400–406
Kong J, Diao Z, Deng X, Zhong H, Yao W, Hu X (2007) Anti-tumor effects of immunotherapeutic peptide on the treatment of hepatocellular carcinoma with HBc carrier. Oncol Rep 18(1):279–285
Holmes JP, Benavides LC, Gates JD, Carmichael MG, Hueman MT, Mittendorf EA, Murray JL, Amin A, Craig D, von Hofe E, Ponniah S, Peoples GE (2008) Results of the first phase I clinical trial of the novel II-key hybrid preventive HER-2/neu peptide (AE37) vaccine. J Clin Oncol 26(20):3426–3433
Cai YG, Fang DC, Chen L et al (2007) Dendritic cells reconstituted with a human heparanase gene induce potent cytotoxic T-cell responses against gastric tumor cells in vitro. Tumor Biol 28(4):238–246
Sommerfeldt N, Beckhove P, Ge Y et al (2006) Heparanase: a new metastasis-associated antigen recognized in breast cancer patients by spontaneously induced memory T lymphocytes. Cancer Res 66:7716–7723
Tang XD, Wan Y, Chen L, Chen T, Yu ST, Xiong Z, Fang DC, Liang GP, Yang SM (2008) H-2Kb-restricted CTL epitopes from mouse heparanase elicit an antitumor immune response in vivo. Cancer Res 68(5):1529–1537
Chen T, Tang XD, Wan Y, Chen L, Yu ST, Xiong Z, Fang DC, Liang GP, Yang SM (2008) HLA-A2-restricted cytotoxic T lymphocyte epitopes from human heparanase as novel targets for broad-spectrum tumor immunotherapy. Neoplasia 10(9):977–986
Arnold B, Hämmerling GJ (1991) MHC class-I trans-genic mice. Annu Rev Immunol 9(1):297–322
Vitiello AD, Marchesini J, Furze LA, Sherman RW (1991) Analysis of the HLA-restricted influenza-specific cytotoxic T lymphocyte response in transgenic mice carrying a chimeric human-mouse class I major histocompatibility complex. J Exp Med 173(4):1007–1015
Chen L, Tang XD, Yu ST, Ai ZH, Fang DC, Cai YG, Luo YH, Liang GP, Yang SM (2009) Induction of anti-tumour immunity by dendritic cells transduced with hTERT recombinant adenovirus in mice. J Pathol 217(5):685–692
Alexander J, Sidney J, Southwood S, Ruppert J, OseroV C, Maewal A (1994) Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides. Immunity 1(1):751–761
Boon T, Old LJ (1997) Cancer tumor antigens. Curr Opin Immunol 9(5):681–683
Pardoll DM (1998) Cancer vaccines. Nat Med 4(5):525–531
Storkus WJ, Herrem C, Kawabe M, Cohen PA, Bukowski RM, Finke JH, Wesa AK (2007) Improving immunotherapy by conditionally enhancing MHC class I presentation of tumor antigen-derived peptide epitopes. Crit Rev Immunol 27(5):485–493
Morris LF, Ribas A (2007) Therapeutic cancer vaccines. Surg Oncol Clin N Am 16(4):819–831
Schmitz M, Bornhäuser M, Ockert D, Rieber EP (2002) Cancer immunotherapy: novel strategies and clinical experiences. Trends Immunol 23(9):428–429
Vieweg J, Jackson A (2004) Antigenic targets for renal cell carcinoma immunotherapy. Expert Opin Biol Ther 4(11):1791–1801
Acknowledgments
This study is supported by grants from the National Program on Key Basic Research Project of China (973 Program) (No.2010CB529406), the National Nature Science Foundation of China (No. 30800520), the Key Project of Science and Technology of Chongqing (CSTC, 2008AB5002) and the Chongqing Science Fund for Distinguished Young Scholars (CSTC, 2009BA5045).
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X.-D. Tang, G. P. Liang and C. Li contributed equally to this work.
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Tang, XD., Liang, GP., Li, C. et al. Cytotoxic T lymphocyte epitopes from human heparanase can elicit a potent anti-tumor immune response in mice. Cancer Immunol Immunother 59, 1041–1047 (2010). https://doi.org/10.1007/s00262-010-0829-x
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DOI: https://doi.org/10.1007/s00262-010-0829-x