Skip to main content
SpringerLink
Log in

Tumor expression of B7-H4 predicts poor survival of patients suffering from gastric cancer

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

Abstract

To establish the prognostic value of B7-H4 expression by tumor cells in gastric cancer patients, we evaluated the association of B7-H4 expression with clinicopathologic factors and overall survival of gastric cancer patients. A retrospective cohort study including 156 gastric cancer patients was performed in the present report. Immunohistochemical assay was used to evaluate the expression of B7-H4 in the surgical specimens of gastric cancer tissues. Multi-univariate COX model was then used to evaluate the association of B7-H4 expression with the patients’ survival and clinicopathological parameters. B7-H4 expression in the gastric cancer cells was observed in about 44.9% gastric cancer specimens. Univariate analysis demonstrated that there was no correlation between B7-H4 expression and sex, age, histological type, pathological grade or tumor size. In contrast, B7-H4 expression correlated positively with cancer invasiveness and lymph node metastasis. In addition, the median overall survival time of patients with lower B7-H4 expression was 13 months longer than that of patients with higher expression (χ2 = 12.38, P < 0.0001), and the median disease-free survival time of patients with lower B7-H4 expression was significantly longer than that of patients with higher expression (33 vs. 16 months, χ2 = 14.977, P < 0.0001). After adjustment for other confounding factors, the COX model analysis indicated that the death risk was significantly higher in patients with higher B7-H4 expression than those with lower expression (RR = 1.85, 95% CI = 1.15–2.96). The present study demonstrated that higher B7-H4 expression in cancer cells was associated with poor prognosis of gastric cancer patients. This is consistent with the idea that B7-H4 promotes cancer progression, likely via inhibition of anti-tumor immune responses.

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

References

  1. Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ (2009) Gastric cancer. Lancet 374:477–490 (PubMed:19625077)

    Article  PubMed  Google Scholar 

  2. Yeh JM, Kuntz KM, Ezzati M, Goldie SJ (2009) Exploring the cost-effectiveness of Helicobacter pylori screening to prevent gastric cancer in China in anticipation of clinical trial results. Int J Cancer 124:157–166 (PubMed:18823009)

    Article  CAS  PubMed  Google Scholar 

  3. Lee JH, Ryu KW, Kook MC, Lee JY, Kim CG, Choi IJ, Kim SK, Jang S, Park SR, Kim YW, Nam BH, Bae JM (2008) Feasibility of laparoscopic sentinel basin dissection for limited resection in early gastric cancer. J Surg Oncol 98:331–335 (PubMed:18646047)

    Article  PubMed  Google Scholar 

  4. Valentini V, Cellini F, Minsky BD, Mattiucci GC, Balducci M, D’Agostino G, D’Angelo E, Dinapoli N, Nicolotti N, Valentini C, La Torre G (2009) Survival after radiotherapy in gastric cancer: systematic review and meta-analysis. Radiother Oncol 92:176–183 (PubMed:19586672)

    Article  PubMed  Google Scholar 

  5. Sun P, Xiang JB, Chen ZY (2009) Meta-analysis of adjuvant chemotherapy after radical surgery for advanced gastric cancer. Br J Surg 96:26–33 (PubMed:19016271)

    Article  CAS  PubMed  Google Scholar 

  6. Jiang J, Xu N, Wu C, Deng H, Lu M, Li M, Xu B, Wu J, Wang R, Xu J, Nilsson-Ehle P (2006) Treatment of advanced gastric cancer by chemotherapy combined with autologous cytokine-induced killer cells. Anticancer Res 26:2237–2242 (PubMed:16821594)

    CAS  PubMed  Google Scholar 

  7. Morabito A, Carillio G, Longo R (2009) Systemic treatment of gastric cancer. Crit Rev Oncol Hematol 70:216–234 (PubMed:18829344)

    Article  PubMed  Google Scholar 

  8. Varadhachary G, Ajani JA (2005) Gastric cancer. Clin Adv Hematol Oncol 3:118–124 (PubMed:16166979)

    PubMed  Google Scholar 

  9. Zou W, Chen L (2008) Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 8:467–477 (PubMed:18500231)

    Article  CAS  PubMed  Google Scholar 

  10. Aunoble B, Sanches R, Didier E, Bignon YJ (2000) Major oncogenes and tumor suppressor genes involved in epithelial ovarian cancer (review). Int J Oncol 16:567–576 (PubMed:10675491)

    CAS  PubMed  Google Scholar 

  11. Nicosia SV, Bai W, Cheng JQ, Coppola D, Kruk PA (2003) Oncogenic pathways implicated in ovarian epithelial cancer. Hematol Oncol Clin North Am 17:927–943 (PubMed:12959183)

    Article  PubMed  Google Scholar 

  12. Carreno BM, Collins M (2003) BTLA: a new inhibitory receptor with a B7-like ligand. Trends Immunol 24:524–527 (PubMed:14552835)

    Article  CAS  PubMed  Google Scholar 

  13. Wang S, Chen L (2004) Co-signaling molecules of the B7-CD28 family in positive and negative regulation of T lymphocyte responses. Microbes Infect 6:759–766 (PubMed:15207823)

    Article  CAS  PubMed  Google Scholar 

  14. Tringler B, Zhuo S, Pilkington G, Torkko KC, Singh M, Lucia MS, Heinz DE, Papkoff J, Shroyer KR (2005) B7-H4 is highly expressed in ductal and lobular breast cancer. Clin Cancer Res 11:1842–1848 (PubMed:15756008)

    Article  CAS  PubMed  Google Scholar 

  15. Choi IH, Zhu G, Sica GL, Strome SE, Cheville JC, Lau JS, Zhu Y, Flies DB, Tamada K, Chen L (2003) Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family. J Immunol 171:4650–4654 (PubMed:14568939)

    CAS  PubMed  Google Scholar 

  16. Sun Y, Wang Y, Zhao J, Gu M, Giscombe R, Lefvert AK, Wang X (2006) B7-H3 and B7-H4 expression in non-small cell lung cancer. Lung Cancer 53:143–151 (PubMed:16782226)

    Article  PubMed  Google Scholar 

  17. Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P, Brumlik M, Cheng P, Curiel T, Myers L, Lackner A, Alvarez X, Ochoa A, Chen L, Zou W (2006) B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med 203:871–881 (PubMed:16606666)

    Article  CAS  PubMed  Google Scholar 

  18. Kryczek I, Wei S, Zhu G, Myers L, Mottram P, Cheng P, Chen L, Coukos G, Zou W (2007) Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Cancer Res 67:8900–8905 (PubMed:17875732)

    Article  CAS  PubMed  Google Scholar 

  19. Xue Q, Luan XY, Gu YZ, Wu HY, Zhang GB, Yu GH, Zhu HT, Wang M, Dong W, Geng YJ, Zhang XG (2010) The negative co-signaling molecule B7-H4 is expressed by human bone marrow-derived mesenchymal stem cells and mediates its T-cell modulatory activity. Stem Cells Dev 19:27–38 (PubMed:19788399)

    Google Scholar 

  20. Yuan CL, Xu JF, Tong J, Yang H, He FR, Gong Q, Xiong P, Duan L, Fang M, Tan Z, Xu Y, Chen YF, Zheng F, Gong FL (2009) B7-H4 transfection prolongs beta-cell graft survival. Transpl Immunol 21:143–149 (PubMed:19361556)

    Article  CAS  PubMed  Google Scholar 

  21. Sun Y, Liu J, Cui X (2006) Clinical significance of expression of B7-H4 in colon and rectal cancer tissues. J Shandong Univ (Health Sci) 44:590–592

    Google Scholar 

  22. De Vita F, Orditura M, Matano E, Bianco R, Carlomagno C, Infusino S, Damiano V, Simeone E, Diadema MR, Lieto E, Castellano P, Pepe S, De Placido S, Galizia G, Di Martino N, Ciardiello F, Catalano G, Bianco AR (2005) A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients. Br J Cancer 92:1644–1649 (PubMed:15856038)

    Article  PubMed  Google Scholar 

  23. Soslow RA, Dannenberg AJ, Rush D, Woerner BM, Khan KN, Masferrer J, Koki AT (2000) COX-2 is expressed in human pulmonary, colonic, and mammary tumors. Cancer 89:2637–2645 (PubMed:11135226)

    Article  CAS  PubMed  Google Scholar 

  24. Hao L, Zhang C, Qiu Y, Wang L, Luo Y, Jin M, Zhang Y, Guo TB, Matsushima K, Zhang Y (2007) Recombination of CXCR4, VEGF, and MMP-9 predicting lymph node metastasis in human breast cancer. Cancer Lett 253:34–42 (PubMed:17306924)

    Article  CAS  PubMed  Google Scholar 

  25. Kamimura Y, Kobori H, Piao J, Hashiguchi M, Matsumoto K, Hirose S, Azuma M (2009) Possible involvement of soluble B7-H4 in T cell-mediated inflammatory immune responses. Biochem Biophys Res Commun 389:349–353 (PubMed:19723502)

    Article  CAS  PubMed  Google Scholar 

  26. Aparicio T, Boige V, Sabourin JC, Crenn P, Ducreux M, Le Cesne A, Bonvalot S (2004) Prognostic factors after surgery of primary resectable gastrointestinal stromal tumours. Eur J Surg Oncol 30:1098–1103 (PubMed:15522557)

    Article  CAS  PubMed  Google Scholar 

  27. Prasad DV, Richards S, Mai XM, Dong C (2003) B7S1, a novel B7 family member that negatively regulates T cell activation. Immunity 18:863–873 (PubMed:12818166)

    Article  CAS  PubMed  Google Scholar 

  28. Sica GL, Choi IH, Zhu G, Tamada K, Wang SD, Tamura H, Chapoval AI, Flies DB, Bajorath J, Chen L (2003) B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity 18:849–861 (PubMed:12818165)

    Article  CAS  PubMed  Google Scholar 

  29. Zang X, Loke P, Kim J, Murphy K, Waitz R, Allison JP (2003) B7x: a widely expressed B7 family member that inhibits T cell activation. Proc Natl Acad Sci USA 100:10388–10392 (PubMed:12920180)

    Article  CAS  PubMed  Google Scholar 

  30. Tringler B, Liu W, Corral L, Torkko KC, Enomoto T, Davidson S, Lucia MS, Heinz DE, Papkoff J, Shroyer KR (2006) B7-H4 overexpression in ovarian tumors. Gynecol Oncol 100:44–52 (PubMed:16256178)

    Article  CAS  PubMed  Google Scholar 

  31. Simon I, Liu Y, Krall KL, Urban N, Wolfert RL, Kim NW, McIntosh MW (2007) Evaluation of the novel serum markers B7-H4, Spondin 2, and DcR3 for diagnosis and early detection of ovarian cancer. Gynecol Oncol 106:112–118 (PubMed:17490732)

    Article  CAS  PubMed  Google Scholar 

  32. Thompson RH, Zang X, Lohse CM, Leibovich BC, Slovin SF, Reuter VE, Cheville JC, Blute ML, Russo P, Kwon ED, Allison JP (2008) Serum-soluble B7x is elevated in renal cell carcinoma patients and is associated with advanced stage. Cancer Res 68:6054–6058 (PubMed:18676826)

    Article  CAS  PubMed  Google Scholar 

  33. Krambeck AE, Thompson RH, Dong H, Lohse CM, Park ES, Kuntz SM, Leibovich BC, Blute ML, Cheville JC, Kwon ED (2006) B7-H4 expression in renal cell carcinoma and tumor vasculature: associations with cancer progression and survival. Proc Natl Acad Sci USA 103:10391–10396 (PubMed:16798883)

    Article  CAS  PubMed  Google Scholar 

  34. Zang X, Thompson RH, Al-Ahmadie HA, Serio AM, Reuter VE, Eastham JA, Scardino PT, Sharma P, Allison JP (2007) B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome. Proc Natl Acad Sci USA 104:19458–19463 (PubMed:18042703)

    Article  CAS  PubMed  Google Scholar 

  35. Wu CP, Jiang JT, Tan M, Zhu YB, Ji M, Xu KF, Zhao JM, Zhang GB, Zhang XG (2006) Relationship between co-stimulatory molecule B7-H3 expression and gastric carcinoma histology and prognosis. World J Gastroenterol 12:457–459 (PubMed:16489649)

    CAS  PubMed  Google Scholar 

  36. Wu C, Zhu Y, Jiang J, Zhao J, Zhang XG, Xu N (2006) Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem 108:19–24 (PubMed:16530813)

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Haifeng Deng, Mingyang Lu, Bin Xu, Yan Tan, Min Li, Jian Liu, Zhengguang Li and Yi Zhou provided excellent technical assistance. This research project was supported by the National Natural Science Foundation of China (NSFC) (30950022, 30972703 and 30872176) and Society or Developing Plans, Department of Science and Technology, Changzhou (BS20092019).

Conflict of interest

The authors declare that they have no competing or financial interests regarding this paper.

Author information

Authors and Affiliations

  1. Department of Tumor Biological Treatment, The Third Affiliated Hospital, Soochow University, 213003, Changzhou, China

    Jingting Jiang, Changping Wu, Lujun Chen & Xiao Zheng

  2. Institute of Biotechnology, Key Laboratory of Clinical Immunology of Jiangsu Province, Soochow University, 215123, Suzhou, China

    Jingting Jiang, Yibei Zhu, Jing Sun & Xueguang Zhang

  3. Department of Immunology, University of Pittsburgh School of Medicine, E1047 BST, 200 Lothrop Street, Pittsburgh, PA, 15261, USA

    Yibei Zhu & Binfeng Lu

  4. Department of Medicine, Soochow University, 215123, Suzhou, China

    Yueping Shen & Wenxiang Wei

Authors
  1. Jingting Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yibei Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Changping Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yueping Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wenxiang Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lujun Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xiao Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jing Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Binfeng Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Xueguang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Binfeng Lu or Xueguang Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jiang, J., Zhu, Y., Wu, C. et al. Tumor expression of B7-H4 predicts poor survival of patients suffering from gastric cancer. Cancer Immunol Immunother 59, 1707–1714 (2010). https://doi.org/10.1007/s00262-010-0900-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00262-010-0900-7

Keywords

Search

Navigation