Top

Published in:

Open Access 01-12-2014 | Translational Research and Biomarkers

Expression of B7-H3, a Potential Factor of Tumor Immune Evasion in Combination with the Number of Regulatory T Cells, Affects Against Recurrence-Free Survival in Breast Cancer Patients

Authors: N. Maeda, MD, K. Yoshimura, MD, PhD, S. Yamamoto, MD, PhD, A. Kuramasu, MD, PhD, M. Inoue, MS, N. Suzuki, MD, PhD, Y. Watanabe, MD, Y. Maeda, MD, R. Kamei, MD, R. Tsunedomi, PhD, Y. Shindo, MD, M. Inui, MD, PhD, K. Tamada, MD, PhD, S. Yoshino, MD, PhD, S. Hazama, MD, PhD, M. Oka, MD, PhD

Published in: Annals of Surgical Oncology | Special Issue 4/2014

Abstract

Background

In the tumor microenvironment, factors inhibiting the targeting of cancer cells by activated T cells have recently been noted. B7-H3 belongs to the B7 superfamily of immune regulatory ligands and plays an important role in the adaptive immune response of co-inhibitory/stimulatory factors in regulating T cells. However, the degree to which B7-H3 directly affects tumor immune evasion mechanisms remains unclear, particularly in patients with breast cancer. Regulatory T cells (Tregs) are known as a key player in the inhibition of immune mechanisms. The present study demonstrated that expression of B7-H3 on tumor cells and the number of Tregs in the tumor microenvironment independently affected prognosis in breast cancer patients.

Methods

We immunohistochemically investigated the presence of B7-H3 and forkhead box P3 (Foxp3)-positive Tregs in pathological specimens from 90 patients with breast cancer.

Results

Positive B7-H3 expression was associated with shorter recurrence-free survival (RFS) (p = 0.014). A higher percentage of Foxp3-positive cells also correlated with shorter RFS (p = 0.039). Multivariate analysis showed B7-H3 as an independent factor on RFS. Foxp3 expression in tumor-infiltrating lymphocytes (TILs) correlated significantly with larger tumor size (>2 cm), expression of human epidermal growth factor receptor 2 (HER2), and higher nuclear grade (p = 0.003, p < 0.001, p = 0.001, respectively). No correlation was identified between expression of B7-H3 and the percentage of Foxp3-positive TILs.

Conclusions

B7-H3 and Foxp3 can be regarded as markers of poor prognosis in breast cancer. These expressions were not correlated, suggesting that B7-H3 expression plays an independent role in tumor immune evasion, regardless of Tregs.

Sun X, Vale M, Leung E, Kanwar JR, Gupta R, Krissansen GW. Mouse B7-H3 induces antitumor immunity. Gene Ther. 2003;10(20):1728–34.PubMedCrossRef

Caras I, Grigorescu A, Stavaru C, et al. Evidence for immune defects in breast and lung cancer patients. Cancer Immunol Immunother. 2004;53(12):1146–52.PubMedCrossRef

Pockaj BA, Basu GD, Pathangey LB, et al. Reduced T-cell and dendritic cell function is related to cyclo-oxygenase-2 overexpression and prostaglandin E2 secretion in patients with breast cancer. Ann Surg Oncol. 2004;11(3):328–39.PubMedCrossRef

Zang X, Allison JP. The B7 family and cancer therapy: costimulation and coinhibition. Clin Cancer Res. 2007;13(18 Pt 1):5271–9.PubMedCrossRef

Zang X, Sullivan PS, Soslow RA, et al. Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas. Mod Pathol. 2010;23(8):1104–12.PubMedCentralPubMedCrossRef

Sun Y, Wang Y, Zhao J, et al. B7-H3 and B7-H4 expression in non-small-cell lung cancer. Lung Cancer. 2006;53(2):143–51.PubMedCrossRef

Wu CP, Jiang JT, Tan M, et al. Relationship between co-stimulatory molecule B7-H3 expression and gastric carcinoma histology and prognosis. World J Gastroenterol. 2006;12(3):457–9.PubMedCentralPubMed

Roth TJ, Sheinin Y, Lohse CM, et al. B7-H3 ligand expression by prostate cancer: a novel marker of prognosis and potential target for therapy. Cancer Res. 2007;67(16):7893–900.PubMedCrossRef

Yamato I, Sho M, Nomi T, et al. Clinical importance of B7-H3 expression in human pancreatic cancer. Br J Cancer. 2009;101(10):1709–16.PubMedCentralPubMedCrossRef

10.

Loos M, Hedderich DM, Ottenhausen M, et al. Expression of the costimulatory molecule B7-H3 is associated with prolonged survival in human pancreatic cancer. BMC Cancer. 2009;9:463.PubMedCentralPubMedCrossRef

11.

Crispen PL, Sheinin Y, Roth TJ, et al. Tumor cell and tumor vasculature expression of B7-H3 predict survival in clear cell renal cell carcinoma. Clin Cancer Res. 2008;14(16):5150–7.PubMedCentralPubMedCrossRef

12.

Sun J, Chen LJ, Zhang GB, et al. Clinical significance and regulation of the costimulatory molecule B7-H3 in human colorectal carcinoma. Cancer Immunol Immunother. 2010;59(8):1163–71.PubMedCrossRef

13.

Suh WK, Gajewska BU, Okada H, et al. The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. Nat Immunol. 2003;4(9):899–906.PubMedCrossRef

14.

Chapoval AI, Ni J, Lau JS, et al. B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol. 2001;2(3):269–74.PubMedCrossRef

15.

Leitner J, Klauser C, Pickl WF, et al. B7-H3 is a potent inhibitor of human T-cell activation: no evidence for B7-H3 and TREML2 interaction. Eur J Immunol. 2009;39(7):1754–64.PubMedCentralPubMedCrossRef

16.

Lupu CM, Eisenbach C, Lupu AD, et al. Adenoviral B7-H3 therapy induces tumor specific immune responses and reduces secondary metastasis in a murine model of colon cancer. Oncol Rep. 2007;18(3):745–8.PubMed

17.

Arigami T, Narita N, Mizuno R, et al. B7-h3 ligand expression by primary breast cancer and associated with regional nodal metastasis. Ann Surg. 2010;252(6):1044–51.PubMedCrossRef

18.

Coffer PJ, Burgering BM. Forkhead-box transcription factors and their role in the immune system. Nat Rev Immunol. 2004;4(11):889–99.PubMedCrossRef

19.

Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057–61.PubMedCrossRef

20.

Liyanage UK, Moore TT, Joo HG, et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J Immunol. 2002;169(5):2756–61.PubMedCrossRef

21.

Sasada T, Kimura M, Yoshida Y, Kanai M, Takabayashi A. CD4+CD25+ regulatory T cells in patients with gastrointestinal malignancies. Cancer. 2003;98(5):1089–99.PubMedCrossRef

22.

Miller AM, Lundberg K, Özenci V, et al. CD4+CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. J Immunol. 2006;177(10):7398–405.PubMedCrossRef

23.

Viguier M, Lemaître F, Verola O, et al. Foxp3 Expressing CD4+CD25high regulatory T cells are overrepresented in human metastatic melanoma lymph nodes and inhibit the function of infiltrating T cells. J Immunol. 2004;173(2):1444–53.PubMedCrossRef

24.

Kawaida H, Kono K, Takahashi A, et al. Distribution of CD4+CD25high regulatory T-cells in tumor-draining lymph nodes in patients with gastric cancer. J Surg Res. 2005;124(1):151–7.PubMedCrossRef

25.

Woo EY, Chu CS, Goletz TJ, et al. Regulatory CD4+CD25+ T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 2001;61(12):4766–72.PubMed

26.

Merlo A, Casalini P, Carcangiu ML, et al. FOXP3 expression and overall survival in breast cancer. J Clin Oncol. 2009;27(11):1746–52.PubMedCrossRef

27.

Bates GJ, Fox SB, Han C, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006;24(34):5373–80.PubMedCrossRef

28.

Bloom HJ, Richardson WW. Histological grading and prognosis in breast cancer: a study of 1409 cases of which 359 have been followed for 15 years. Br J Cancer. 1957;11(3):359–77.PubMedCentralPubMedCrossRef

29.

Erkan M, Kleeff J, Esposito I, et al. Loss of BNIP3 expression is a late event in pancreatic cancer contributing to chemoresistance and worsened prognosis. Oncogene. 2005;24(27):4421–32.PubMedCrossRef

30.

Shin T, Yoshimura K, Shin T, et al. In vivo costimulatory role of B7-DC in tuning T helper cell 1 and cytotoxic T lymphocyte responses. J Exp Med. 2005;201(10):1531–41.PubMedCentralPubMedCrossRef

31.

Castriconi R, Dondero A, Augugliaro R, et al. Identification of 4Ig-B7-H3 as a neuroblastoma-associated molecule that exerts a protective role from an NK cell-mediated lysis. Proc Natl Acad Sci USA. 2004;101(34):12640–5.PubMedCentralPubMedCrossRef

32.

Yuan H, Wei X, Zhang G, Li C, Zhang X, Hou J. B7-H3 over expression in prostate cancer promotes tumor cell progression. J Urol. 2011;186(3):1093–9.PubMedCrossRef

33.

Arigami T, Uenosono Y, Hirata M, Yanagita S, Ishigami S, Natsugoe S. B7-H3 expression in gastric cancer: a novel molecular blood marker for detecting circulating tumor cells. Cancer Sci. 2011;102(5):1019–24.PubMedCrossRef

34.

Brunner A, Hinterholzer S, Riss P, Heinze G, Brustmann H. Immunoexpression of B7-H3 in endometrial cancer: relation to tumor T-cell infiltration and prognosis. Gynecol Oncol. 2012;124(1):105–11.PubMedCrossRef

35.

Petersen RP, Campa MJ, Sperlazza J, et al. Tumor infiltrating Foxp3+ regulatory T-cells are associated with recurrence in pathologic stage I NSCLC patients. Cancer. 2006;107(12):2866–72.PubMedCrossRef

36.

Liyanage UK, Goedegebuure PS, Moore TT, et al. Increased prevalence of regulatory T cells (Treg) is induced by pancreas adenocarcinoma. J Immunother. 2006;29(4):416–24.PubMedCrossRef

37.

Hiraoka N, Onozato K, Kosuge T, Hirohashi S. Prevalence of FOXP3+ regulatory T cells increases during the progression of pancreatic ductal adenocarcinoma and its premalignant lesions. Clin Cancer Res. 2006;12(18):5423–34.PubMedCrossRef

38.

Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10(9):942–9.PubMedCrossRef

39.

Generali D, Bates G, Berruti A, et al. Immunomodulation of FOXP3+ regulatory T cells by the aromatase inhibitor letrozole in breast cancer patients. Clin Cancer Res. 2009;15(3):1046–51.PubMedCrossRef

40.

West NR, Kost SE, Martin SD, et al. Tumour-infiltrating FOXP3(+) lymphocytes are associated with cytotoxic immune responses and good clinical outcome in oestrogen receptor-negative breast cancer. Br J Cancer. 2013;108(1):155–62.PubMedCentralPubMedCrossRef

41.

Yoshimura K, Laird LS, Chia CY, et al. Live attenuated Listeria monocytogenes effectively treats hepatic colorectal cancer metastases and is strongly enhanced by depletion of regulatory T cells. Cancer Res. 2007;67(20):10058–66.PubMedCrossRef

42.

Brenton JD, Carey LA, Ahmed AA, Caldas C. Molecular classification and molecular forecasting of breast cancer: ready for clinical application? J Clin Oncol. 2005;23(29):7350–60.PubMedCrossRef

43.

Cheang MCU, Chia SK, Voduc D, et al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009;101(10):736–50.PubMedCentralPubMedCrossRef

Title: Expression of B7-H3, a Potential Factor of Tumor Immune Evasion in Combination with the Number of Regulatory T Cells, Affects Against Recurrence-Free Survival in Breast Cancer Patients
Authors: N. Maeda, MD
K. Yoshimura, MD, PhD
S. Yamamoto, MD, PhD
A. Kuramasu, MD, PhD
M. Inoue, MS
N. Suzuki, MD, PhD
Y. Watanabe, MD
Y. Maeda, MD
R. Kamei, MD
R. Tsunedomi, PhD
Y. Shindo, MD
M. Inui, MD, PhD
K. Tamada, MD, PhD
S. Yoshino, MD, PhD
S. Hazama, MD, PhD
M. Oka, MD, PhD
Publication date: 01-12-2014
Publisher: Springer US
Published in: Annals of Surgical Oncology / Issue Special Issue 4/2014
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI: https://doi.org/10.1245/s10434-014-3564-2

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Expression of B7-H3, a Potential Factor of Tumor Immune Evasion in Combination with the Number of Regulatory T Cells, Affects Against Recurrence-Free Survival in Breast Cancer Patients

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Special Issue 4/2014

Genetic Variations in STK11, PRKAA1, and TSC1 Associated with Prognosis for Patients with Colorectal Cancer

Association of miRNA-related Genetic Polymorphisms and Prognosis in Patients with Esophageal Squamous Cell Carcinoma

Epithelial-to-Mesenchymal Transition (EMT) in Intraductal Papillary Mucinous Neoplasm (IPMN) is Associated with High Tumor Grade and Adverse Outcomes

Loss of CD44 and SOX2 Expression is Correlated with a Poor Prognosis in Esophageal Adenocarcinoma Patients

Noninvasive Diagnosis and Evaluation of Curative Surgery for Gastric Cancer by Using NMR-based Metabolomic Profiling

Anti-Prokineticin1 (PROK1) Monoclonal Antibody Suppresses Angiogenesis and Tumor Growth in Colorectal Cancer