Skip to main content

Advertisement

SpringerLink
Log in

Characterization of human CD4 helper T cell responses against Aurora kinase A

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

Abstract

Aurora kinase A (Aurora-A) is a cell cycle-associated serine–threonine kinase that is overexpressed by various types of cancer and is highly associated with poor prognosis. Since the expression of Aurora-A in normal tissues has been shown to be significantly lower as compared to tumor cells, this protein is being considered as a potential tumor-associated antigen for developing immunotherapies. The goal in the present study was to identify CD4 helper T lymphocyte (HTL) epitopes for Aurora-A for the design of T cell-based immunotherapies against Aurora-A-expressing tumors. Synthetic peptides corresponding to potential HTL epitopes were identified from Aurora-A and used to stimulate CD4 T lymphocytes in vitro to generate antigen-specific HTL clones that were evaluated for antigen specificity, MHC restriction and for their ability to interact with Aurora-A-expressing tumor cells. The results show that two peptides (Aurora-A161–175 and Aurora-A233–247) were effective in generating HTL responses that were restricted by more than one MHC class II allele (i.e., promiscuous responses). The CD4 HTL clones were able to directly recognize Aurora-A-expressing tumor cells in an antigen-specific and MHC class II-restricted manner and some of the clones displayed cytolytic activity toward Aurora-A + tumor cells. Both of these peptides were capable of stimulating in vitro T cell responses in patients with bladder cancer.

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
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

Abbreviations

APC:

Antigen-presenting cell(s)

Aurora-A:

Aurora kinase A

DC:

Dendritic cell(s)

HTL:

Helper T lymphocyte(s)

TAA:

Tumor-associated antigen(s)

References

  1. Alexander J, Sidney J, Southwood S, Ruppert J, Oseroff C, Maewal A, Snoke K, Serra HM, Kubo RT, Sette A et al (1994) Development of high potency universal DR-restricted helper epitopes by modification of high affinity DR-blocking peptides. Immunity 1:751–761

    Article  CAS  PubMed  Google Scholar 

  2. Bischoff JR, Anderson L, Zhu Y, Mossie K, Ng L, Souza B, Schryver B, Flanagan P, Clairvoyant F, Ginther C, Chan CS, Novotny M, Slamon DJ, Plowman GD (1998) A homologue of Drosophila aurora kinase is oncogenic and amplified in human colorectal cancers. EMBO J 17:3052–3065

    Article  CAS  PubMed  Google Scholar 

  3. Boehm U, Klamp T, Groot M, Howard JC (1997) Cellular responses to interferon-gamma. Annu Rev Immunol 15:749–795

    Article  CAS  PubMed  Google Scholar 

  4. Bui HH, Sidney J, Peters B, Sathiamurthy M, Sinichi A, Purton KA, Mothe BR, Chisari FV, Watkins DI, Sette A (2005) Automated generation and evaluation of specific MHC binding predictive tools: ARB matrix applications. Immunogenetics 57:304–314

    Article  CAS  PubMed  Google Scholar 

  5. Carvajal RD, Tse A, Schwartz GK (2006) Aurora kinases: new targets for cancer therapy. Clin Cancer Res 12:6869–6875

    Article  CAS  PubMed  Google Scholar 

  6. Gautschi O, Heighway J, Mack PC, Purnell PR, Lara PN Jr, Gandara DR (2008) Aurora kinases as anticancer drug targets. Clin Cancer Res 14:1639–1648

    Article  CAS  PubMed  Google Scholar 

  7. Giet R, Petretti C, Prigent C (2005) Aurora kinases, aneuploidy and cancer, a coincidence or a real link? Trends Cell Biol 15:241–250

    Article  CAS  PubMed  Google Scholar 

  8. Giuntoli RL 2nd, Lu J, Kobayashi H, Kennedy R, Celis E (2002) Direct costimulation of tumor-reactive CTL by helper T cells potentiate their proliferation, survival, and effector function. Clin Cancer Res 8:922–931

    PubMed  Google Scholar 

  9. Hamada M, Yakushijin Y, Ohtsuka M, Kakimoto M, Yasukawa M, Fujita S (2003) Aurora2/BTAK/STK15 is involved in cell cycle checkpoint and cell survival of aggressive non-Hodgkin’s lymphoma. Br J Haematol 121:439–447

    Article  CAS  PubMed  Google Scholar 

  10. Hung K, Hayashi R, Lafond-Walker A, Lowenstein C, Pardoll D, Levitsky H (1998) The central role of CD4(+) T cells in the antitumor immune response. J Exp Med 188:2357–2368

    Article  CAS  PubMed  Google Scholar 

  11. Kennedy R, Celis E (2008) Multiple roles for CD4+ T cells in anti-tumor immune responses. Immunol Rev 222:129–144

    Article  CAS  PubMed  Google Scholar 

  12. Kimura M, Matsuda Y, Yoshioka T, Okano Y (1999) Cell cycle-dependent expression and centrosome localization of a third human aurora/Ipl1-related protein kinase, AIK3. J Biol Chem 274:7334–7340

    Article  CAS  PubMed  Google Scholar 

  13. Kobayashi H, Celis E (2008) Peptide epitope identification for tumor-reactive CD4 T cells. Curr Opin Immunol 20:221–227

    Article  CAS  PubMed  Google Scholar 

  14. Kobayashi H, Nagato T, Takahara M, Sato K, Kimura S, Aoki N, Azumi M, Tateno M, Harabuchi Y, Celis E (2008) Induction of EBV-latent membrane protein 1-specific MHC class II-restricted T-cell responses against natural killer lymphoma cells. Cancer Res 68:901–908

    Article  CAS  PubMed  Google Scholar 

  15. Kobayashi H, Wood M, Song Y, Appella E, Celis E (2000) Defining promiscuous MHC class II helper T-cell epitopes for the HER2/neu tumor antigen. Cancer Res 60:5228–5236

    CAS  PubMed  Google Scholar 

  16. Kurahashi T, Miyake H, Hara I, Fujisawa M (2007) Significance of Aurora-A expression in renal cell carcinoma. Urol Oncol 25:128–133

    CAS  PubMed  Google Scholar 

  17. Landen CN Jr, Lin YG, Immaneni A, Deavers MT, Merritt WM, Spannuth WA, Bodurka DC, Gershenson DM, Brinkley WR, Sood AK (2007) Overexpression of the centrosomal protein Aurora-A kinase is associated with poor prognosis in epithelial ovarian cancer patients. Clin Cancer Res 13:4098–4104

    Article  CAS  PubMed  Google Scholar 

  18. Lassmann S, Shen Y, Jutting U, Wiehle P, Walch A, Gitsch G, Hasenburg A, Werner M (2007) Predictive value of Aurora-A/STK15 expression for late stage epithelial ovarian cancer patients treated by adjuvant chemotherapy. Clin Cancer Res 13:4083–4091

    Article  CAS  PubMed  Google Scholar 

  19. Lee EC, Frolov A, Li R, Ayala G, Greenberg NM (2006) Targeting Aurora kinases for the treatment of prostate cancer. Cancer Res 66:4996–5002

    Article  CAS  PubMed  Google Scholar 

  20. Li D, Zhu J, Firozi PF, Abbruzzese JL, Evans DB, Cleary K, Friess H, Sen S (2003) Overexpression of oncogenic STK15/BTAK/Aurora A kinase in human pancreatic cancer. Clin Cancer Res 9:991–997

    CAS  PubMed  Google Scholar 

  21. Malumbres M, Barbacid M (2007) Cell cycle kinases in cancer. Curr Opin Genet Dev 17:60–65

    Article  CAS  PubMed  Google Scholar 

  22. Manfredi MG, Ecsedy JA, Meetze KA, Balani SK, Burenkova O, Chen W, Galvin KM, Hoar KM, Huck JJ, LeRoy PJ, Ray ET, Sells TB, Stringer B, Stroud SG, Vos TJ, Weatherhead GS, Wysong DR, Zhang M, Bolen JB, Claiborne CF (2007) Antitumor activity of MLN8054, an orally active small-molecule inhibitor of Aurora A kinase. Proc Natl Acad Sci USA 104:4106–4111

    Article  CAS  PubMed  Google Scholar 

  23. Marumoto T, Zhang D, Saya H (2005) Aurora-A—a guardian of poles. Nat Rev Cancer 5:42–50

    Article  CAS  PubMed  Google Scholar 

  24. Miyoshi I, Kubonishi I, Yoshimoto S, Akagi T, Ohtsuki Y, Shiraishi Y, Nagata K, Hinuma Y (1981) Type C virus particles in a cord T-cell line derived by co-cultivating normal human cord leukocytes and human leukaemic T cells. Nature 294:770–771

    Article  CAS  PubMed  Google Scholar 

  25. Nishimura T, Iwakabe K, Sekimoto M, Ohmi Y, Yahata T, Nakui M, Sato T, Habu S, Tashiro H, Sato M, Ohta A (1999) Distinct role of antigen-specific T helper type 1 (Th1) and Th2 cells in tumor eradication in vivo. J Exp Med 190:617–627

    Article  CAS  PubMed  Google Scholar 

  26. Ochi T, Fujiwara H, Suemori K, Azuma T, Yakushijin Y, Hato T, Kuzushima K, Yasukawa M (2009) Aurora-A kinase: a novel target of cellular immunotherapy for leukemia. Blood 113:66–74

    Article  CAS  PubMed  Google Scholar 

  27. Omiya R, Buteau C, Kobayashi H, Paya CV, Celis E (2002) Inhibition of EBV-induced lymphoproliferation by CD4(+) T cells specific for an MHC class II promiscuous epitope. J Immunol 169:2172–2179

    CAS  PubMed  Google Scholar 

  28. Qin Z, Blankenstein T (2000) CD4 + T cell–mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFN gamma receptor expression by nonhematopoietic cells. Immunity 12:677–686

    Article  CAS  PubMed  Google Scholar 

  29. Rosenberg SA (2001) Progress in human tumour immunology and immunotherapy. Nature 411:380–384

    Article  CAS  PubMed  Google Scholar 

  30. Sen S, Zhou H, White RA (1997) A putative serine/threonine kinase encoding gene BTAK on chromosome 20q13 is amplified and overexpressed in human breast cancer cell lines. Oncogene 14:2195–2200

    Article  CAS  PubMed  Google Scholar 

  31. Sen S, Zhou H, Zhang RD, Yoon DS, Vakar-Lopez F, Ito S, Jiang F, Johnston D, Grossman HB, Ruifrok AC, Katz RL, Brinkley W, Czerniak B (2002) Amplification/overexpression of a mitotic kinase gene in human bladder cancer. J Natl Cancer Inst 94:1320–1329

    CAS  PubMed  Google Scholar 

  32. Shi Y, Reiman T, Li W, Maxwell CA, Sen S, Pilarski L, Daniels TR, Penichet ML, Feldman R, Lichtenstein A (2007) Targeting aurora kinases as therapy in multiple myeloma. Blood 109:3915–3921

    Article  CAS  PubMed  Google Scholar 

  33. Tyler RK, Shpiro N, Marquez R, Eyers PA (2007) VX-680 inhibits Aurora A and Aurora B kinase activity in human cells. Cell Cycle 6:2846–2854

    CAS  PubMed  Google Scholar 

  34. van der Burg SH, Menon AG, Redeker A, Franken KL, Drijfhout JW, Tollenaar RA, Hartgrink HH, van de Velde CJ, Kuppen PJ, Melief CJ, Offringa R (2003) Magnitude and polarization of P53-specific T-helper immunity in connection to leukocyte infiltration of colorectal tumors. Int J Cancer 107:425–433

    Article  PubMed  Google Scholar 

  35. Xu HT, Ma L, Qi FJ, Liu Y, Yu JH, Dai SD, Zhu JJ, Wang EH (2006) Expression of serine threonine kinase 15 is associated with poor differentiation in lung squamous cell carcinoma and adenocarcinoma. Pathol Int 56:375–380

    Article  CAS  PubMed  Google Scholar 

  36. Zhou H, Kuang J, Zhong L, Kuo WL, Gray JW, Sahin A, Brinkley BR, Sen S (1998) Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nat Genet 20:189–193

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Ministry of Education, Sports, and Culture of Japan grant-in-aid 21590424 (H. Kobayashi), 20390438 (Y. Harabuchi) and supported in part by NIH grant P50CA91956 (E. Celis).

Author information

Authors and Affiliations

  1. Department of Pathology, Asahikawa Medical College, Asahikawa, Japan

    Hiroya Kobayashi, Makoto Azumi, Satoshi Hayashi, Keisuke Sato, Naoko Aoki, Shoji Kimura & Masatoshi Tateno

  2. Department of Urology, Asahikawa Medical College, Asahikawa, Japan

    Hidehiro Kakizaki

  3. Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical College, Asahikawa, Japan

    Toshihiro Nagato & Yasuaki Harabuchi

  4. Department of Oncologic Sciences, University of South Florida, Immunology Program of the Moffitt Cancer Center, 12902 Magnolia Drive, SRB2, Tampa, FL, 33612, USA

    Esteban Celis

  5. Department of Molecular Medicine, University of South Florida, Tampa, FL, 33612, USA

    Esteban Celis

Authors
  1. Hiroya Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Makoto Azumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Satoshi Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Keisuke Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naoko Aoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shoji Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hidehiro Kakizaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Toshihiro Nagato
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yasuaki Harabuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Masatoshi Tateno
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Esteban Celis
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Esteban Celis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kobayashi, H., Azumi, M., Hayashi, S. et al. Characterization of human CD4 helper T cell responses against Aurora kinase A. Cancer Immunol Immunother 59, 1029–1039 (2010). https://doi.org/10.1007/s00262-010-0826-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-010-0826-0

Keywords

Search

Navigation