Skip to main content

Advertisement

SpringerLink
Log in

Maintenance of WT1 expression in tumor cells is associated with a good prognosis in malignant glioma patients treated with WT1 peptide vaccine immunotherapy

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

Abstract

We have previously revealed the overexpression of Wilms’ tumor gene 1 (WT1) in malignant glioma and developed WT1 peptide vaccine cancer immunotherapy. A phase II clinical trial indicated the clinical efficacy of the WT1 peptide vaccine for recurrent malignant glioma. Here, we aimed to investigate the immunological microenvironment in glioma tissues before and after WT1 peptide vaccine treatment. Paired tissue samples were obtained from 20 malignant glioma patients who had received the WT1 peptide vaccine for > 3 months and experienced tumor progression, confirmed radiographically and/or clinically, during vaccination. We discovered that the expression of WT1 and HLA class I antigens in the tumor cells significantly decreased after vaccination. Maintenance of WT1 expression, which is the target molecule of immunotherapy, in tumor cells during the vaccination period was significantly associated with a longer progression-free and overall survival. A high expression of HLA class I antigens and low CD4+/CD8+ tumor-infiltrating lymphocytes (TIL) ratio in pre-vaccination specimens, were also associated with a good prognosis. No statistically significant difference existed in the number of infiltrating CD3+ or CD8+ T cells between the pre- and post-vaccination specimens, whereas the number of infiltrating CD4+ T cells significantly decreased in the post-vaccination specimens. This study provides insight into the mechanisms of intra-tumoral immune reaction/escape during WT1 peptide vaccine treatment and suggests potential clinical strategies for cancer immunotherapy.

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

Similar content being viewed by others

Abbreviations

AA:

Anaplastic astrocytoma

AE:

Anaplastic ependymoma

AOA:

Anaplastic oligoastrocytoma

CI:

Confidence intervals

CR:

Complete response

CTL:

Cytotoxic T lymphocyte

GBM:

Glioblastoma

HLA:

Human leukocyte antigen

HR:

Hazard ratio

IL:

Interleukin

OS-WT1:

Overall survival from the start of the WT1 vaccination

PD:

Progressive disease

PD-1:

Programmed cell death-1

PD-L1:

Programmed cell death ligand-1

PFS-WT1:

Progression-free survival from the start of the WT1 vaccination

PR:

Partial response

SD:

Stable disease

TAA:

Tumor-associated antigen

TGF:

Transforming Growth Factor

TIL:

Tumor-infiltrating lymphocytes

Treg:

Regulatory T cell

TRM:

Tissue-resident memory T cell

TSA:

Tumor-specific antigen

WHO:

World Health Organization

WT1:

Wilms’ tumor gene 1

References

  1. Wen PY, Kesari S (2008) Malignant gliomas in adults. N Engl J Med 359:492–507

    Article  CAS  PubMed  Google Scholar 

  2. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109. https://doi.org/10.1007/s00401-007-0243-4

    Article  PubMed  PubMed Central  Google Scholar 

  3. Stupp R, Mason WP, Van Den Bent MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996

    Article  CAS  PubMed  Google Scholar 

  4. Burnet F (1970) The concept of immunological surveillance. In: Schwartz RS (ed) Immunological Aspects of Neoplasia. Karger Publishers, pp 1–27

    Google Scholar 

  5. Dunn GP, Old LJ, Schreiber RD (2004) The three Es of cancer immunoediting. Annu Rev Immunol 22:329–360. https://doi.org/10.1146/annurev.immunol.22.012703.104803

    Article  CAS  PubMed  Google Scholar 

  6. van Oijen M, Bins A, Elias S et al (2004) On the role of melanoma-specific CD8+ T-cell immunity in disease progression of advanced-stage melanoma patients. Clin Cancer Res: Off J Am Assoc Cancer Res 10:4754–4760. https://doi.org/10.1158/1078-0432.CCR-04-026010/14/4754[pii]

    Article  Google Scholar 

  7. Swann JB, Smyth MJ (2007) Immune surveillance of tumors. J Clin Invest 117:1137–1146. https://doi.org/10.1172/JCI31405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shimizu K, Uemura H, Yoshikawa M, Yoshida K, Hirao Y, Iwashima K, Saga S, Yoshikawa K (2003) Induction of antigen specific cellular immunity by vaccination with peptides from MN/CA IX in renal cell carcinoma. Oncol Rep 10:1307–1311

    CAS  PubMed  Google Scholar 

  9. Oji Y, Suzuki T, Nakano Y et al (2004) Overexpression of the Wilms’ tumor gene W T1 in primary astrocytic tumors. Cancer Sci 95:822–827. https://doi.org/10.1111/j.1349-7006.2004.tb02188.x

    Article  CAS  PubMed  Google Scholar 

  10. Hashiba T, Izumoto S, Kagawa N, Suzuki T, Hashimoto N, Maruno M, Yoshimine T (2007) Expression of WT1 protein and correlation with cellular proliferation in glial tumors. Neurol Med Chir (Tokyo) 47(4):165–70. https://doi.org/10.2176/nmc.47.165

    Article  Google Scholar 

  11. Izumoto S, Tsuboi A, Oka Y et al (2008) Phase II clinical trial of Wilms tumor 1 peptide vaccination for patients with recurrent glioblastoma multiforme. J Neurosurg 108:963–971. https://doi.org/10.3171/jns/2008/108/5/0963

    Article  CAS  PubMed  Google Scholar 

  12. Morita S, Oka Y, Tsuboi A et al (2006) A phase I/II trial of a WT1 (Wilms’ tumor gene) peptide vaccine in patients with solid malignancy: safety assessment based on the phase I data. Jpn J Clin Oncol 36:231–236. https://doi.org/10.1093/jjco/hyl005

    Article  PubMed  Google Scholar 

  13. Tsuboi A, Oka Y, Udaka K et al (2002) Enhanced induction of human WT1-specific cytotoxic T lymphocytes with a 9-mer WT1 peptide modified at HLA-A*2402-binding residues. Cancer Immunol, Immunother: CII 51:614–620. https://doi.org/10.1007/s00262-002-0328-9

    Article  CAS  PubMed  Google Scholar 

  14. Therasse P, Arbuck SG, Eisenhauer EA et al (2000) New guidelines to evaluate the response to treatment in solid tumors. JNCI: J Natl Cancer Inst 92(3):205–16. https://doi.org/10.1093/jnci/92.3.205

    Article  CAS  PubMed  Google Scholar 

  15. Miyazaki T, Ishikawa E, Matsuda M et al (2017) Assessment of PD-1 positive cells on initial and secondary resected tumor specimens of newly diagnosed glioblastoma and its implications on patient outcome. J Neurooncol 133:277–285. https://doi.org/10.1007/s11060-017-2451-7

    Article  CAS  PubMed  Google Scholar 

  16. Aptsiauri N, Cabrera T, Garcia-Lora A, Lopez-Nevot MA, Ruiz-Cabello F, Garrido F (2007) MHC class I antigens and immune surveillance in transformed cells. Int Rev Cytol. https://doi.org/10.1016/S0074-7696(07)56005-5

    Article  PubMed  Google Scholar 

  17. Perea F, Sánchez-Palencia A, Gómez-Morales M et al (2017) HLA class I loss and PD-L1 expression in lung cancer: impact on T-cell infiltration and immune escape. Oncotarget 9:4120–4133. https://doi.org/10.18632/oncotarget.23469

    Article  PubMed  PubMed Central  Google Scholar 

  18. Blades RA, Keating PJ, McWilliam LJ, George NJ, Stern PL (1995) Loss of HLA class I expression in prostate cancer: implications for immunotherapy. Urology 46:681–687

    Article  CAS  PubMed  Google Scholar 

  19. Facoetti A, Nano R, Zelini P, Morbini P, Benericetti E, Ceroni M, Campoli M, Ferrone S (2005) Human leukocyte antigen and antigen processing machinery component defects in astrocytic tumors. Clin Cancer Res: Off J Am Assoc Cancer Res. https://doi.org/10.1158/1078-0432.CCR-04-2588

    Article  Google Scholar 

  20. Chang CC, Campoli M, Ferrone S (2003) HLA class I defects in malignant lesions: what have we learned? Keio J Med 52:220–229

    Article  CAS  PubMed  Google Scholar 

  21. Gilboa E (1999) How tumors escape immune destruction and what we can do about it. Cancer Immunol Immunother 48:382–385. https://doi.org/10.1007/s002620050590

    Article  CAS  PubMed  Google Scholar 

  22. Slingluff CL Jr, Colella TA, Thompson L et al (2000) Melanomas with concordant loss of multiple melanocytic differentiation proteins: immune escape that may be overcome by targeting unique or undefined antigens. Cancer Immunol Immunother 48:661–672

    Article  CAS  PubMed  Google Scholar 

  23. Khong HT, Wang QJ, Rosenberg SA (2004) Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: tumor escape by antigen loss and loss of MHC expression. J Immunother 27:184–190

    Article  PubMed  PubMed Central  Google Scholar 

  24. Bubeník J (2003) Tumour MHC class I downregulation and immunotherapy. Oncol Rep 10:2005–2008

    PubMed  Google Scholar 

  25. Chiba Y, Hashimoto N, Tsuboi A et al (2010) Prognostic value of WT1 protein expression level and MIB-1 staining index as predictor of response to WT1 immunotherapy in glioblastoma patients. Brain Tumor Pathol 27:29–34. https://doi.org/10.1007/s10014-010-0265-9

    Article  CAS  PubMed  Google Scholar 

  26. Maheswaran S, Englert C, Bennett P, Heinrich G, Haber DA (1995) The WT1 gene product stabilizes p53 and inhibits p53-mediated apoptosis. Genes Dev 9:2143–2156

    Article  CAS  PubMed  Google Scholar 

  27. Sciesielski LK, Kirschner KM, Scholz H, Persson AB (2010) Wilms’ tumor protein Wt1 regulates the Interleukin-10 (IL-10) gene. FEBS Lett 584:4665–4671. https://doi.org/10.1016/j.febslet.2010.10.045

    Article  CAS  PubMed  Google Scholar 

  28. Little M, Wells C (1997) A clinical overview of WT1 gene mutations. Hum Mutat 9:209–225

    Article  CAS  PubMed  Google Scholar 

  29. Lee SB, Haber DA (2001) Wilms tumor and the WT1 gene. Exp Cell Res 264:74–99

    Article  CAS  PubMed  Google Scholar 

  30. Kijima N, Hosen N, Kagawa N, Hashimoto N, Kinoshita M, Oji Y, Sugiyama H, Yoshimine T (2014) Wilms’ tumor 1 is involved in tumorigenicity of glioblastoma by regulating cell proliferation and apoptosis. Anticancer Res 34:61–67

    CAS  PubMed  Google Scholar 

  31. Oji Y, Hashimoto N, Tsuboi A et al (2016) Association of WT1 IgG antibody against WT1 peptide with prolonged survival in glioblastoma multiforme patients vaccinated with WT1 peptide. Int J Cancer 139:1391–1401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Smolders J, Heutinck KM, Fransen NL, Remmerswaal EBM, Hombrink P, Ten Berge IJM, van Lier RAW, Huitinga I, Hamann J (2018) Tissue-resident memory T cells populate the human brain. Nat Commun 9:4593. https://doi.org/10.1038/s41467-018-07053-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Beura LK, Fares-Frederickson NJ, Steinert EM, Scott MC, Thompson EA, Fraser KA, Schenkel JM, Vezys V, Masopust D (2019) CD4+ resident memory T cells dominate immunosurveillance and orchestrate local recall responses. J Exp Med 216:1214–1229. https://doi.org/10.1084/jem.20181365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lin Y, Fujiki F, Katsuhara A et al (2013) HLA-DPB1* 05: 01-restricted WT1332-specific TCR-transduced CD4+ T lymphocytes display a helper activity for WT1-specific CTL induction and a cytotoxicity against leukemia cells. J Immunother 36:159–170

    Article  CAS  PubMed  Google Scholar 

  35. Dresemann G (2010) Temozolomide in malignant glioma. Onco Targets Ther 3:139–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Brandes AA, Franceschi E, Tosoni A et al (2008) MGMT promoter methylation status can predict the incidence and outcome of pseudoprogression after concomitant radiochemotherapy in newly diagnosed glioblastoma patients. J Clin Oncol: Off J Am Soci Clin Oncol 26:2192–2197. https://doi.org/10.1200/jco.2007.14.8163

    Article  Google Scholar 

  37. Arenas-Ramirez N, Sahin D, Boyman O (2018) Epigenetic mechanisms of tumor resistance to immunotherapy. Cell Mol Life Sci 75:4163–4176

    Article  CAS  PubMed  Google Scholar 

  38. Kosoff D, Krueger T, Lang JM (2013) Targeting epigenetic mechanisms for clinical translation: enhancing the efficacy of tumor immunotherapies. Immunotherapy 5:1243–1254

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank all the patients enrolled in our clinical trials and the Center for Medical Research and Education, Graduate School of Medicine, Osaka University, for their support.

Funding

This work was supported by JSPS KAKENHI Grant Numbers JP 16K20008 and JP 25462257.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Chisato Yokota, Naoki Kagawa, Manabu Kinoshita, Noriyuki Kijima & Haruhiko Kishima

  2. Department of Neurosurgery, Osaka International Cancer Institute, 3-1-69, Otemae, Chuo-ku, Osaka-shi, Osaka, 541-8567, Japan

    Koji Takano

  3. Department of Neurosurgery, Osaka Women’s and Children’s Hospital, 840, Murodo‐choIzumi, Osaka, 594‐1101, Japan

    Yasuyoshi Chiba

  4. Department of Functional Diagnostic Science, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Yusuke Oji

  5. Cancer Stem Cell Biology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Yoshihiro Oka

  6. Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Yoshihiro Oka

  7. Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Yoshihiro Oka

  8. Cancer Immunology, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Haruo Sugiyama

  9. Cancer Immunotherapy, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Akihiro Tsuboi

  10. Department of Neurosurgery, Kindai University Nara Hospital, 1248-1, Otsuda-cho, Ikoma city, Nara, 630-0293, Japan

    Shuichi Izumoto

  11. Department of Neurosurgery, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-dori, Hirokoji-agaru, Kamigyo-ku, Kyoto, 602-8566, Japan

    Naoya Hashimoto

Authors
  1. Chisato Yokota
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naoki Kagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Koji Takano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasuyoshi Chiba
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Manabu Kinoshita
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Noriyuki Kijima
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yusuke Oji
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yoshihiro Oka
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Haruo Sugiyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Akihiro Tsuboi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Shuichi Izumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Haruhiko Kishima
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Naoya Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

CY, KT, YC, NK, and NH participated in the conception and design of this study. CY, KT, and YC performed the experiments. NK, AT, YO, YO, SI, HS and NH contributed to patient recruitment, treatment, and clinical data collection. CY, KT, YC, and YO contributed to the statistical analyses. MK, NK, AT, YO, HS, HK, NH, and NK joined the discussion, following which, CY, KT, YO, NH, and NK collectively wrote the manuscript. All authors had contributed towards manuscript revisions and have approved the final manuscript.

Corresponding author

Correspondence to Naoki Kagawa.

Ethics declarations

Conflicts of interest

The authors have no conflicts of interest to declare.

Ethical approval

The study was performed in accordance with the Declaration of Helsinki, Japanese Ethical Guidelines for Clinical Research, and Japanese Guidelines for Medical and Health Research. This trial was registered at the UMIN Clinical Trials Registry as Umin000000933 and Umin000002001. This clinical study was approved by the Ethical Review Board of Osaka University (approval number 07099 and 18193).

Consent for publication

The authors declare that this manuscript is original, has not been published before, and is not currently under consideration for publication elsewhere.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yokota, C., Kagawa, N., Takano, K. et al. Maintenance of WT1 expression in tumor cells is associated with a good prognosis in malignant glioma patients treated with WT1 peptide vaccine immunotherapy. Cancer Immunol Immunother 71, 189–201 (2022). https://doi.org/10.1007/s00262-021-02954-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-021-02954-z

Keywords

Search

Navigation