Skip to main content

Advertisement

SpringerLink
Log in

Identification of a novel HLA-A2-restricted mutated Survivin epitope and induction of specific anti-HCC CTLs that could effectively cross-recognize wild-type Survivin antigen

  • Original Article
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Peptide vaccine based on tumor-associated antigen (TAA), which usually belongs to self-antigen with poor immunogenicity, has been considered as an attractive option for treatment of malignant tumors. The ideal TAA epitopes should have stable affinity to major histocompatibility complex (MHC) molecules and elicit strong anti-tumor immune response. Although point-mutation technology of TAA peptide may increase the binding capability to MHC molecules, some previous studies have revealed that part of the variant peptides results in lymphocyte not to effectively cross-recognize and kill the target tumor expressed wild-type TAA. Here, we designed a novel HLA-A2-restricted mutated TAA Survivin epitope nonapeptide Sur79L2 (KLSSGCAFL) that showed higher binding ability compared to wild-type peptide Sur79 (KHSSGCAFL) in T2-binding assays. To investigate whether Sur79L2 can induce Survivin-specific anti-hepatocellular carcinoma (HCC) response, we stimulated tumor-associated lymphocytes from a HCC patient with Sur79L2 in vitro. IFN-γ release and cytotoxicity assays showed Sur79L2 could effectively cross-recognize and lysis T2 cell plus peptide Sur79 and HCC cell lines (expression of wild-type Survivin antigen) in an HLA-A2-restricted manner. In contrast, peptide Sur95 (ELTLGEFLKL) that has been reported as a very promising anti-tumor epitope in a variety of tumors except HCC were not able to generate detectable cytotoxic immune responses against HCC in this study. Our results suggest that point-mutated peptide Sur79L2 is a new HLA-A2-restricted CTL epitope and may be useful for the immunotherapy for patients with HCC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Finn RS (2010) Development of molecularly targeted therapies in hepatocellular carcinoma: where do we go now? Clin Cancer Res 16:390–397

    Article  PubMed  CAS  Google Scholar 

  2. Klebanoff CA, Acquavella N, Yu Z, Restifo NP (2011) Therapeutic cancer vaccines: are we there yet? Immunol Rev 239:27–44

    Article  PubMed  CAS  Google Scholar 

  3. Palucka K, Ueno H, Banchereau J (2011) Recent developments in cancer vaccines. J Immunol 186:1325–1331

    Article  PubMed  CAS  Google Scholar 

  4. Zerbini A, Pilli M, Soliani P, Ziegler S, Pelosi G, Orlandini A, Cavallo C, Uggeri J, Scandroglio R, Crafa P, Spagnoli GC, Ferrari C, Missale G (2004) Ex vivo characterization of tumor-derived melanoma antigen encoding gene-specific CD8 + cells in patients with hepatocellular carcinoma. J Hepatol 40:102–109

    Article  PubMed  CAS  Google Scholar 

  5. Shang XY, Chen HS, Zhang HG, Pang XW, Qiao H, Peng JR, Qin LL, Fei R, Mei MH, Leng XS, Gnjatic S, Ritter G, Simpson AJ, Old LJ, Chen WF (2004) The spontaneous CD8 + T-cell response to HLA-A2-restricted NY-ESO-1b peptide in hepatocellular carcinoma patients. Clin Cancer Res 10:6946–6955

    Article  PubMed  CAS  Google Scholar 

  6. Butterfield LH, Ribas A, Dissette VB, Lee Y, Yang JQ, De la Rocha P, Duran SD, Hernandez J, Seja E, Potter DM, McBride WH, Finn R, Glaspy JA, Economou JS (2006) A phase I/II trial testing immunization of hepatocellular carcinoma patients with dendritic cells pulsed with four alpha-fetoprotein peptides. Clin Cancer Res 12:2817–2825

    Article  PubMed  CAS  Google Scholar 

  7. Sah NK, Khan Z, Khan GJ, Bisen PS (2006) Structural, functional and therapeutic biology of survivin. Cancer Lett 244:164–171

    Article  PubMed  CAS  Google Scholar 

  8. Yamamoto H, Ngan CY, Monden M (2008) Cancer cells survive with surviving. Cancer Sci 99:1709–1714

    Article  PubMed  CAS  Google Scholar 

  9. Mamori S, Asakura T, Ohkawa K, Tajiri H (2007) Survivin expression in early hepatocellular carcinoma and post-treatment with anti-cancer drug under hypoxic culture condition. World J Gastroenterol 13:5306–5311

    PubMed  CAS  Google Scholar 

  10. Tsuruma T, Iwayama Y, Ohmura T, Katsuramaki T, Hata F, Furuhata T, Yamaguchi K, Kimura Y, Torigoe T, Toyota N, Yagihashi A, Hirohashi Y, Asanuma H, Shimozawa K, Okazaki M, Mizushima Y, Nomura N, Sato N, Hirata K (2008) Clinical and immunological evaluation of anti-apoptosis protein, survivin-derived peptide vaccine in phase I clinical study for patients with advanced or recurrent breast cancer. J Transl Med 6:24

    Article  PubMed  Google Scholar 

  11. Kameshima H, Tsuruma T, Torigoe T, Takahashi A, Hirohashi Y, Tamura Y, Tsukahara T, Ichimiya S, Kanaseki T, Iwayama Y, Sato N, Hirata K (2011) Immunogenic enhancement and clinical effect by type-I interferon of anti-apoptotic protein, survivin-derived peptide vaccine, in advanced colorectal cancer patients. Cancer Sci 102:1181–1187

    Article  PubMed  CAS  Google Scholar 

  12. Honma I, Kitamura H, Torigoe T, Takahashi A, Tanaka T, Sato E, Hirohashi Y, Masumori N, Tsukamoto T, Sato N (2009) Phase I clinical study of anti-apoptosis protein survivin-derived peptide vaccination for patients with advanced or recurrent urothelial cancer. Cancer Immunol Immunother 58:1801–1807

    Article  PubMed  CAS  Google Scholar 

  13. Andersen MH, Pedersen LO, Capeller B, Bröcker EB, Becker JC, thor Straten P (2001) Spontaneous cytotoxic T-cell responses against survivin-derived MHC class I-restricted T-cell epitopes in situ as well as ex vivo in cancer patients. Cancer Res 61:5964–5968

    PubMed  CAS  Google Scholar 

  14. Casati C, Dalerba P, Rivoltini L, Gallino G, Deho P, Rini F, Belli F, Mezzanzanica D, Costa A, Andreola S, Leo E, Parmiani G, Castelli C (2003) The apoptosis inhibitor protein survivin induces tumor-specific CD8 + and CD4 + T cells in colorectal cancer patients. Cancer Res 63:4507–4515

    PubMed  CAS  Google Scholar 

  15. Yu Z, Theoret MR, Touloukian CE, Surman DR, Garman SC, Feigenbaum L, Baxter TK, Baker BM, Restifo NP (2004) Poor immunogenicity of a self/tumor antigen derives from peptide-MHC-I instability and is independent of tolerance. J Clin Invest 114:551–559

    PubMed  CAS  Google Scholar 

  16. McMahan RH, McWilliams JA, Jordan KR, Dow SW, Wilson DB, Slansky JE (2006) Relating TCR-peptide-MHC affinity to immunogenicity for the design of tumor vaccines. J Clin Invest 116:2543–2551

    PubMed  CAS  Google Scholar 

  17. Rizzuto GA, Merghoub T, Hirschhorn-Cymerman D, Liu C, Lesokhin AM, Sahawneh D, Zhong H, Panageas KS, Perales MA, Altan-Bonnet G, Wolchok JD, Houghton AN (2009) Self-antigen-specific CD8 + T cell precursor frequency determines the quality of the antitumor immune response. J Exp Med 206:849–866

    Article  PubMed  CAS  Google Scholar 

  18. Jordan KR, McMahan RH, Kemmler CB, Kappler JW, Slansky JE (2010) Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens. Proc Natl Acad Sci USA 107:4652–4657

    Article  PubMed  CAS  Google Scholar 

  19. 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 61:869–872

    PubMed  CAS  Google Scholar 

  20. Butterfield LH (2007) Recent advances in immunotherapy for hepatocellular cancer. Swiss Med Wkly 137:83–90

    PubMed  CAS  Google Scholar 

  21. Colella TA, Bullock TN, Russell LB, Mullins DW, Overwijk WW, Luckey CJ, Pierce RA, Restifo NP, Engelhard VH (2000) Self-tolerance to the murine homologue of a tyrosinase-derived melanoma antigen: implications for tumor immunotherapy. J Exp Med 91:1221–1232

    Article  Google Scholar 

  22. McWilliams JA, Sullivan RT, Jordan KR, McMahan RH, Kemmler CB, McDuffie M, Slansky JE (2008) Age-dependent tolerance to an endogenous tumor-associated antigen. Vaccine 26:1863–1873

    Article  PubMed  CAS  Google Scholar 

  23. Idenoue S, Hirohashi Y, Torigoe T, Sato Y, Tamura Y, Hariu H, Yamamoto M, Kurotaki T, Tsuruma T, Asanuma H, Kanaseki T, Ikeda H, Kashiwagi K, Okazaki M, Sasaki K, Sato T, Ohmura T, Hata F, Yamaguchi K, Hirata K, Sato N (2005) A potent immunogenic general cancer vaccine that targets survivin, an inhibitor of apoptosis proteins. Clin Cancer Res 11:1474–1482

    Article  PubMed  CAS  Google Scholar 

  24. Wobser M, Keikavoussi P, Kunzmann V, Weininger M, Andersen MH, Becker JC (2006) Complete remission of liver metastasis of pancreatic cancer under vaccination with a HLA-A2 restricted peptide derived from the universal tumor antigen surviving. Cancer Immunol Immunother 55:1294–1298

    Article  PubMed  CAS  Google Scholar 

  25. Fuessel S, Meye A, Schmitz M, Zastrow S, Linné C, Richter K, Löbel B, Hakenberg OW, Hoelig K, Rieber EP, Wirth MP (2006) Vaccination of hormone-refractory prostate cancer patients with peptide cocktail-loaded dendritic cells: results of a phase I clinical trial. Prostate 66:811–821

    Article  PubMed  CAS  Google Scholar 

  26. Sun YC, Shen J, Shen, H, Shao HW, Huang SL (2007) Study of Survivin gene cloning and HLA-A2-restricted CTL epitope prediction in Hela cell line. Chin J Immunol 23:1044–1051 (Chinese)

    Google Scholar 

  27. Bachinsky MM, Guillen DE, Patel SR, Singleton J, Chen C, Soltis DA, Tussey LG (2005) Mapping and binding analysis of peptides derived from the tumor-associated antigen survivin for eight HLA alleles. Cancer Immun 5:6

    PubMed  Google Scholar 

  28. Preta G, Marescotti D, Fortini C, Carcoforo P, Castelli C, Masucci M, Gavioli R (2008) Inhibition of serine-peptidase activity enhances the generation of a survivin-derived HLA-A2-presented CTL epitope in colon-carcinoma cells. Scand J Immunol 68:579–588

    Article  PubMed  CAS  Google Scholar 

  29. Morgan RA, Dudley ME, Wunderlich JR, Hughes MS, Yang JC, Sherry RM, Royal RE, Topalian SL, Kammula US, Restifo NP, Zheng Z, Nahvi A, de Vries CR, Rogers-Freezer LJ, Mavroukakis SA, Rosenberg SA (2006) Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314:126–129

    Article  PubMed  CAS  Google Scholar 

  30. Coccoris M, Straetemans T, Govers C, Lamers C, Sleijfer S, Debets R (2010) T cell receptor (TCR) gene therapy to treat melanoma: lessons from clinical and preclinical studies. Expert Opin Biol Ther 10:547–562

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Dr. Yu Liu of Wuhan University for her helpful reviews and suggestions. This work was supported by the National Major Projects of Science and Technology of China (No. 2009ZX09103-708), National Natural Science Foundation of China (No. 31100664) and Natural Science Foundation of Guangdong Province (No. 10151022401000024).

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. School of Life Science and Biopharmaceutics, Guangdong Pharmaceutical University, 28 E. Rd outside the City of Guangzhou University, Guangzhou, 510006, Guangdong, People’s Republic of China

    Han Shen, Hong-Wei Shao, Feng-Lin Wu, Hui Wang, Zhao-Liang Huang, Juan Shen, Teng Wang, Wen-Feng Zhang & Shu-Lin Huang

  2. Southern Medical University, 1838 North Guangzhou Avenue, Guangzhou, 510515, Guangdong, People’s Republic of China

    Han Shen

  3. Institute of Bio-Pharmaceutical, Guangdong Pharmaceutical University, 28 E. Rd outside the City of Guangzhou University, Guangzhou, 510006, Guangdong, People’s Republic of China

    Hong-Wei Shao, Feng-Lin Wu, Hui Wang, Wen-Feng Zhang & Shu-Lin Huang

  4. Department of Oncology, Guangzhou Panyu Central Hospital, 8 Fuyu Road East, Panyu District, Guangzhou, 511400, Guangdong, People’s Republic of China

    Xiao-Hua Chen

Authors
  1. Han Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hong-Wei Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiao-Hua Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Feng-Lin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhao-Liang Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Juan Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Teng Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wen-Feng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shu-Lin Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shu-Lin Huang.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 10537 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shen, H., Shao, HW., Chen, XH. et al. Identification of a novel HLA-A2-restricted mutated Survivin epitope and induction of specific anti-HCC CTLs that could effectively cross-recognize wild-type Survivin antigen. Cancer Immunol Immunother 62, 393–403 (2013). https://doi.org/10.1007/s00262-012-1323-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-012-1323-4

Keywords

Search

Navigation