Skip to main content

Advertisement

SpringerLink
Log in

Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers

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

Abstract

Purpose

The programmed death-1 (PD-1)/B7-H1 (also called PD-L1) pathway negatively regulates T cell activation and has been suggested to play an important role in regulating antitumor host immunity. To investigate the clinical significance of B7-H1 expression to the tumor grade and postoperative prognosis of patients with urothelial cancer, we analyzed the relationship between B7-H1 expression and various clinicopathological features and postoperative prognosis.

Experimental design

Sixty-five urothelial cancer cases were examined. B7-H1 expression in tumors and the numbers and phenotypes of tumor-infiltrating lymphocytes were evaluated by immunohistochemistry and flow cytometry.

Results

A substantial expression of B7-H1 was observed in all urothelial cancers investigated. Tumor specimens from patients with higher WHO grade or primary tumor classifications showed significantly higher percentages of tumor-associated B7-H1. Tumor-associated B7-H1 expression was significantly associated with a high frequency of postoperative recurrence and poor survival rate. Furthermore, multivariate analysis indicated that tumor-associated B7-H1 was more significant prognostic factor than WHO grade.

Conclusions

Our results demonstrate that the aberrant expression of B7-H1 in urothelial cancer is associated with aggressive tumors, suggesting a regulatory role of tumor-associated B7-H1 in antitumor immunity. Therefore, the manipulation of tumor-associated B7-H1 may become a beneficial target for immunotherapy in human urothelial 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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Tsujihashi H, Matsuda H, Uejima S, Akiyama T, Kurita T (1988) Immunocompetence of tissue infiltrating lymphocytes in bladder tumors. J Urol 140:890–894

    PubMed  CAS  Google Scholar 

  2. Tsujihashi H, Matsuda H, Uejima S, Akiyama T, Kurita T (1989) Immunoresponse of tissue infiltrating lymphocytes in bladder tumors. J Urol 141:1467–1470

    PubMed  CAS  Google Scholar 

  3. Lipponen PK, Eskelinen MJ, Jauhiainen K, Harju E, Terho R (1993) Tumor-infiltrating lymphocytes as an independent prognostic factor in transitional cell bladder cancer. Eur J Cancer 29A:69–75

    Article  Google Scholar 

  4. Patard JJ, Saint F, Velotti F, Abbou CC, Chopin DK (1998) Immune response following intravesical Bacillus Calmette-Guerin instillations in superficial bladder cancer: a review. Urol Res 26:155–159

    Article  PubMed  CAS  Google Scholar 

  5. Dong H, Chen L (2003) B7-H1 pathway and its role in the evasion of tumor immunity. J Mol Med 81:281–287

    PubMed  CAS  Google Scholar 

  6. Blank C, Gajewski TF, Mackensen A (2005) Interaction of PD-L1 on tumor cells with PD-1 on tumor-specific T cells as a mechanism of immune evasion: implications for tumor immunotherapy. Cancer Immunol Immunother 54:307–314

    Article  PubMed  CAS  Google Scholar 

  7. Okazaki T, Iwai Y, Honjo T (2002) New regulatory co-receptors: inducible co-stimulator and PD-1. Curr Opin Immunol 14:779–782

    Article  PubMed  CAS  Google Scholar 

  8. Agata Y, Kawasaki A, Nishimura H, Ishida Y, Tsubata T, Yagita H, Honjo T (1996) Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 8:765–772

    Article  PubMed  CAS  Google Scholar 

  9. Nishimura H, Nose M, Hirai H, Minato N, Honjo T (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–151

    Article  PubMed  CAS  Google Scholar 

  10. Nishimura H, Minato N, Nakano T, Honjo T (1998) Immunological studies on PD-1 deficient mice: implication of PD-1 as a negative regulator for B cell responses. Int Immunol 10:1563–1572

    Article  PubMed  CAS  Google Scholar 

  11. Nishimura H, Okazaki T, Tanaka Y, Nakatani K, Hara M, Matsunori A, Sasayama S, Mizoguchi A, Hiai H, Minato N, Honjo T (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:319–322

    Article  PubMed  CAS  Google Scholar 

  12. Dong H, Zhu G, Tamada K, Chen L (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 5:1365–1369

    Article  PubMed  CAS  Google Scholar 

  13. Latchman Y, Wood CR, Chernova T, Chaudhary D, Borde M, Chernova I, Iwai Y, Long AJ, Brown JA, Nunes R, Greenfield EA, Bourque K, Boussiotis VA, Carter LL, Carreno BM, Malenkovich N, Nishimura H, Okazaki T, Honjo T, Sharpe AH, Freeman GJ (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2:261–268

    Article  PubMed  CAS  Google Scholar 

  14. Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, Nishimura H, Fitz LJ, Malenkovich N, Okazaki T, Byrne MC, Horton HF, Fouser L, Carter L, Ling V, Bowman MR, Carreno BM, Collins M, Wood CR, Honjo T (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192:1027–1034

    Article  PubMed  CAS  Google Scholar 

  15. Tamura H, Dong H, Zhu G, Sica GL, Flies DB, Tamada K, Chen L (2001) B7-H1 costimulation preferentially enhances CD28-independent T-help cell function. Blood 97:1809–1816

    Article  PubMed  CAS  Google Scholar 

  16. Youngnak-Piboonratanakit P, Tsushima F, Otsuki N, Igarashi H, Machida U, Iwai H, Takahashi Y, Omura K, Yokozeki H, Azuma M (2004) The expression of B7-H1 on keratinocytes in chronic inflammatory mucocutaneous disease and its regulatory role. Immunol Lett 94:215–222

    Article  PubMed  CAS  Google Scholar 

  17. Blank C, Brown I, Peterson AC, Spiotto M, Iwai Y, Honjo T, Gajewski TF (2004) PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res 64:1140–1145

    Article  PubMed  CAS  Google Scholar 

  18. Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, Roche PC, Lu J, Zhu G, Tamada K, Lennon VA, Celis E, Chen L (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8:793–800

    PubMed  CAS  Google Scholar 

  19. Wintterle S, Screiner B, Mitsdoerffer M, Schneider D, Chen L, Meyermann R, Weller M, Wiendl H (2003) Expression of the B7-related molecule B7-H1 by glioma cells: a potential mechanism of immune paralysis. Cancer Res 63:7462–7467

    PubMed  CAS  Google Scholar 

  20. Tsuda M, Matsumoto K, Inoue H, Matsumura M, Nakano T, Mori A, Azuma M, Nakanishi Y (2005) Expression of B7-H1 and B7-DC on the airway epithelium is enhanced by double-stranded RNA. Biochem Biophys Res Commun 330:263–270

    Article  PubMed  CAS  Google Scholar 

  21. Brown JA, Dorfman DM, Ma FR, Sullivan EL, Munoz O, Wood CR, Greenfield EA, Freeman GJ (2003) Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol 170:1257–1266

    PubMed  CAS  Google Scholar 

  22. Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P, Krzysiek R, Knutson KL, Daniel B, Zimmermann MC, David O, Burow M, Gordon A, Dhurandhar N, Myers L, Berggern R, Hemminiki A, Alvarez RD, Emilie D, Curiel DT, Chen L, Zou W (2003) Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 9:562–567

    Article  PubMed  CAS  Google Scholar 

  23. Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N (2002) Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 99:12293–12297

    Article  PubMed  CAS  Google Scholar 

  24. Konishi J, Yamazaki K, Azuma M, Kinoshita I, Dosaka-Akita H, Nishimura M (2004) B7-H1 expression on non-small cell lung cancer cells and its relationship with tumor-infiltrating lymphocytes and their PD-1 expression. Clin Cancer Res 10:5094–5100

    Article  PubMed  CAS  Google Scholar 

  25. Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeba N, Mizuno T, Yoriki R, Kashizuka H, Yane K, Tsushima F, Otsuki N, Yagita H, Azuma M, Nakajima Y (2005) Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res 11:2947–2953

    Article  PubMed  CAS  Google Scholar 

  26. Thompson RH, Webster WS, Cheville JC, Lohse CM, Dong H, Leibovich BC, Kuntz SM, Sengupta S, Kwon ED, Blute ML (2005) B7-H1 glycoprotein blockade: a novel strategy to enhance immunotherapy in patients with renal cell carcinoma. Urology 66:10–14

    Article  PubMed  Google Scholar 

  27. Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, Krejci KG, Lobo JR, Sengupta S, Chen L, Zincke H, Blute ML, Strome SE, Leibovich BC, Kwon ED (2004) Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci USA 101:17174–17179

    Article  PubMed  CAS  Google Scholar 

  28. Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, Sengupta S, Frank I, Parker AS, Zincke H, Blute ML, Sebo TJ, Cheville JC, Kwon ED (2006) Tumor B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-up. Cancer Res 66:3381–3385

    Article  PubMed  CAS  Google Scholar 

  29. Carter L, Fouser LA, Jussif J, Fitz L, Deng B, Wood CR, Collins M, Honjo T, Freeman GJ, Carreno BM (2002) PD-1: PD-L inhibitory pathway affects both CD4 (+) and CD8 (+) T cells and is overcome by IL-2. Eur J Immunol 32:634–643

    Article  PubMed  CAS  Google Scholar 

  30. Youngnak P, Kozono Y, Kozono H, Iwai H, Otsuki N, Jin H, Omura K, Yagita H, Pardoll DM, Chen L, Azuma M (2003) Differential binding properties of B7-H1 and B7-DC to programmed death-1. Biochem Biophys Res Commun 307:672–677

    Article  PubMed  CAS  Google Scholar 

  31. Tsushima F, Tanaka K, Otsuki N, Youngnak P, Iwai H, Omura K, Azuma M (2006) Predominant expression of B7-H1 and its immunoregulatory roles in oral squamous cell carcinoma. Oral Oncol 42:268–274

    Article  PubMed  CAS  Google Scholar 

  32. Mehal WZ, Azzaroli F, Crispe IN (2001) Antigen presentation by liver cells controls intrahepatic T cell trapping, whereas bone marrow-derived cells preferentially promote intrahepatic T cell apoptosis. J Immunol 167:667–673

    PubMed  CAS  Google Scholar 

  33. Strome SE, Dong H, Tamura H, Voss SG, Flies DB, Tamada K, Salomao D, Cheville J, Hirano F, Lin W, Kasperbauer JL, Ballman KV, Chen L (2003) B7-H1 blockade augments adoptive T-cell immunotherapy for squamous cell carcinoma. Cancer Res 63:6501–6505

    PubMed  CAS  Google Scholar 

  34. Schmitt WE, Stassar MJ, Schmitt W, Little M, Cochlovius B (2001) In vitro induction of a bladder cancer-specific T-cell response by mRNA-transfected dendritic cells. J Cancer Res Clin Oncol 127:203–206

    Article  PubMed  CAS  Google Scholar 

  35. Nishiyama T, Tachibana M, Horiguchi Y, Nakamura K, Ikebe Y, Takesako K, Murai M (2001) Immunotherapy of bladder cancer using autologous dendritic cells pulsed with human lymphocyte antigen-A24-specific MAGE-3 peptide. Clin Cancer Res 7:23–31

    PubMed  CAS  Google Scholar 

  36. Hsu FJ, Komarovskaya M (2002) CTLA4 blockade maximizes antitumor T-cell activation by dendritic cells presenting idiotype protein or opsonized anti-CD20 antibody-coated lymphoma cells. J Immunother 25:455–268

    Article  PubMed  CAS  Google Scholar 

  37. Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M, Suzuki Y, Shintaku I, Nagura H, Ohtani H (2001) Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 61:5132–5136

    PubMed  CAS  Google Scholar 

  38. Zisman A, Pantuck AJ, Dorey F, Said JW, Shvarts O, Quintana D, Gitlitz BJ, deKernion JB, Figlin RA, Belldegrun AS (2001) Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol 19:1649–1657

    PubMed  CAS  Google Scholar 

  39. Motzer RJ, Bander NH, Nanus DM (1996) Renal-cell carcinoma. N Engl J Med 335:865–875

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Urology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1, Honjo, Kumamoto, 860-8556, Japan

    Juro Nakanishi, Yoshihiro Wada & Shoichi Ueda

  2. Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Koichiro Matsumoto

  3. Department of Molecular Immunology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan

    Miyuki Azuma

  4. Medical Information Technology and Administration Planning, Kumamoto University Hospital, Kumamoto, Japan

    Ken Kikuchi

Authors
  1. Juro Nakanishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoshihiro Wada
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Koichiro Matsumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miyuki Azuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ken Kikuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shoichi Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yoshihiro Wada.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nakanishi, J., Wada, Y., Matsumoto, K. et al. Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother 56, 1173–1182 (2007). https://doi.org/10.1007/s00262-006-0266-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-006-0266-z

Keywords

Search

Navigation