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01-11-2012 | Original Article

B7-H3 is expressed in human hepatocellular carcinoma and is associated with tumor aggressiveness and postoperative recurrence

Authors: Tai-Wei Sun, Qiang Gao, Shuang-Jian Qiu, Jian Zhou, Xiao-Ying Wang, Yong Yi, Jie-Yi Shi, Yong-Feng Xu, Ying-Hong Shi, Kang Song, Yong-Sheng Xiao, Jia Fan

Published in: Cancer Immunology, Immunotherapy | Issue 11/2012

Abstract

B7-H3, a novel B7 family member, positively or negatively regulates T-cell responses. We investigated the clinical relevance and prognostic significance of B7-H3 in hepatocellular carcinoma (HCC). Western blotting showed B7-H3 upregulation in 17 of 24 (70.8 %) HCC tissues compared with nontumor liver tissues (p = 0.028). B7-H3 immunostaining on tissue microarrays containing 240 HCC patient samples indicated that 225 (93.8 %) tumors had aberrant B7-H3 expression, with strong intensity in 79 (32.9 %) cases, whereas B7-H3 expression in peritumor liver cells was weak in most cases (226; 94.2 %). Notably, patients with high/moderate tumor cell B7-H3 expression showed significantly poorer survival (p = 0.009) and increased recurrence (p = 0.002). After multivariable adjustment, high/moderate B7-H3 expression remained significant for an increased risk of recurrence (hazard ratio = 1.79; 95 % confidence interval = 1.19–2.70; p = 0.005). B7-H3 expression correlated with invasive phenotypes like vascular invasion and advanced tumor stage, and the metastatic potential of HCC cell lines. Flow cytometry showed that B7-H3 expression is inversely correlated with proliferation and interferon-γ production by infiltrating T cells. Interferon-γ stimulation significantly upregulated B7-H3 expression in HCC cells in vitro, implicating B7-H3 expression as a feedback mechanism to evade anti-tumor immunity. Importantly, the prognostic value of B7-H3 expression was validated in an independent cohort of 206 HCC patients. Collectively, our data suggest that B7-H3 was abundantly expressed in HCC and was associated with adverse clinicopathologic features and poor outcome. Thus, B7-H3 represents an attractive target for diagnostic and therapeutic manipulation in human HCC.

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Jemal A, Bray F, Center M, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90PubMedCrossRef

Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc J-F, de Oliveira AC, Santoro A, Raoul J-L, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz J-F, Borbath I, Haussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J, The SISG (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4):378–390PubMedCrossRef

Palmer DH, Midgley RS, Mirza N, Torr EE, Ahmed F, Steele JC, Steven NM, Kerr DJ, Young LS, Adams DH (2009) A phase II study of adoptive immunotherapy using dendritic cells pulsed with tumor lysate in patients with hepatocellular carcinoma. Hepatology 49(1):124–132PubMedCrossRef

Zou W, Chen L (2008) Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol 8(6):467–477PubMedCrossRef

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(4):871–881PubMedCrossRef

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 U S A 104(49):19458–19463PubMedCrossRef

Gao Q, Wang XY, Qiu SJ, Yamato I, Sho M, Nakajima Y, Zhou J, Li BZ, Shi YH, Xiao YS, Xu Y, Fan J (2009) Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res 15(3):971–979PubMedCrossRef

Chapoval AI, Ni J, Lau JS, Wilcox RA, Flies DB, Liu D, Dong H, Sica GL, Zhu G, Tamada K, Chen L (2001) B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol 2(3):269–274PubMedCrossRef

Hofmeyer KA, Ray A, Zang X (2008) The contrasting role of B7-H3. Proc Natl Acad Sci U S A 105(30):10277–10278PubMedCrossRef

10.

Hashiguchi M, Kobori H, Ritprajak P, Kamimura Y, Kozono H, Azuma M (2008) Triggering receptor expressed on myeloid cell-like transcript 2 (TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses. Proc Natl Acad Sci U S A 105(30):10495–10500PubMedCrossRef

11.

Suh WK, Gajewska BU, Okada H, Gronski MA, Bertram EM, Dawicki W, Duncan GS, Bukczynski J, Plyte S, Elia A, Wakeham A, Itie A, Chung S, Da Costa J, Arya S, Horan T, Campbell P, Gaida K, Ohashi PS, Watts TH, Yoshinaga SK, Bray MR, Jordana M, Mak TW (2003) The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. Nat Immunol 4(9):899–906PubMedCrossRef

12.

Crispen PL, Sheinin Y, Roth TJ, Lohse CM, Kuntz SM, Frigola X, Thompson RH, Boorjian SA, Dong H, Leibovich BC, Blute ML, Kwon ED (2008) Tumor cell and tumor vasculature expression of B7-H3 predict survival in clear cell renal cell carcinoma. Clin Cancer Res 14(16):5150–5157PubMedCrossRef

13.

Roth TJ, Sheinin Y, Lohse CM, Kuntz SM, Frigola X, Inman BA, Krambeck AE, McKenney ME, Karnes RJ, Blute ML, Cheville JC, Sebo TJ, Kwon ED (2007) B7-H3 ligand expression by prostate cancer: a novel marker of prognosis and potential target for therapy. Cancer Res 67(16):7893–7900PubMedCrossRef

14.

Arigami T, Narita N, Mizuno R, Nguyen L, Ye X, Chung A, Giuliano AE, Hoon DS (2010) B7-h3 ligand expression by primary breast cancer and associated with regional nodal metastasis. Ann Surg 252(6):1044–1051PubMedCrossRef

15.

Loos M, Hedderich DM, Ottenhausen M, Giese NA, Laschinger M, Esposito I, Kleeff J, Friess H (2009) Expression of the costimulatory molecule B7-H3 is associated with prolonged survival in human pancreatic cancer. BMC Cancer 9:463PubMedCrossRef

16.

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(3):457–459PubMed

17.

Quandt D, Fiedler E, Boettcher D, Marsch W, Seliger B (2011) B7-H4 expression in human melanoma: its association with patients’ survival and anti tumor immune response. Clin Cancer Res 17(10):3100–3111PubMedCrossRef

18.

Li Y, Tang ZY, Ye SL, Liu YK, Chen J, Xue Q, Gao DM, Bao WH (2001) Establishment of cell clones with different metastatic potential from the metastatic hepatocellular carcinoma cell line MHCC97. World J Gastroenterol 7(5):630–636PubMed

19.

Li Y, Tang Y, Ye L, Liu B, Liu K, Chen J, Xue Q (2003) Establishment of a hepatocellular carcinoma cell line with unique metastatic characteristics through in vivo selection and screening for metastasis-related genes through cDNA microarray. J Cancer Res Clin Oncol 129(1):43–51PubMedCrossRef

20.

Xu YF, Yi Y, Qiu SJ, Gao Q, Li YW, Dai CX, Cai MY, Ju MJ, Zhou J, Zhang BH, Fan J (2010) PEBP1 downregulation is associated to poor prognosis in HCC related to hepatitis B infection. J Hepatol 53(5):872–879PubMedCrossRef

21.

Sun HC, Zhang W, Qin LX, Zhang BH, Ye QH, Wang L, Ren N, Zhuang PY, Zhu XD, Fan J, Tang ZY (2007) Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma. J Hepatol 47(5):684–690PubMedCrossRef

22.

Greene FL, Page DL, Fleming ID et al (2002) AJCC cancer staging manual, 6th edn. Springer, Chicago, pp 131–144

23.

Unitt E, Rushbrook SM, Marshall A, Davies S, Gibbs P, Morris LS, Coleman N, Alexander GJ (2005) Compromised lymphocytes infiltrate hepatocellular carcinoma: the role of T-regulatory cells. Hepatology 41(4):722–730PubMedCrossRef

24.

Zang X, Sullivan P, Soslow R, Waitz R, Reuter V, Wilton A, Thaler H, Arul M, Slovin S, Wei J (2010) Tumor associated endothelial expression of B7-H3 predicts survival in ovarian carcinomas. Mod Pathol 23(8):1104–1112PubMedCrossRef

25.

Luo L, Qiao H, Meng F, Dong X, Zhou B, Jiang H, Kanwar J, Krissansen G, Sun X (2006) Arsenic trioxide synergizes with B7H3-mediated immunotherapy to eradicate hepatocellular carcinomas. Int J Cancer 118(7):1823–1830PubMedCrossRef

26.

Ma L, Luo L, Qiao H, Dong X, Pan S, Jiang H, Krissansen GW, Sun X (2007) Complete eradication of hepatocellular carcinomas by combined vasostatin gene therapy and B7H3-mediated immunotherapy. J Hepatol 46(1):98–106PubMedCrossRef

27.

Lupu CM, Eisenbach C, Lupu AD, Kuefner MA, Hoyler B, Stremmel W, Encke J (2007) Adenoviral B7-H3 therapy induces tumor specific immune responses and reduces secondary metastasis in a murine model of colon cancer. Oncol Rep 18(3):745–748PubMed

28.

Sun J, Chen L, Zhang G, Jiang J, Zhu M, Tan Y, Wang H, Lu B, Zhang X (2010) Clinical significance and regulation of the costimulatory molecule B7-H3 in human colorectal carcinoma. Cancer Immunol Immunother 59(8):1163–1171PubMedCrossRef

29.

Leitner J, Klauser C, Pickl WF, Stockl J, Majdic O, Bardet AF, Kreil DP, Dong C, Yamazaki T, Zlabinger G, Pfistershammer K, Steinberger P (2009) B7-H3 is a potent inhibitor of human T-cell activation: No evidence for B7-H3 and TREML2 interaction. Eur J Immunol 39(7):1754–1764PubMedCrossRef

30.

Yamato I, Sho M, Nomi T, Akahori T, Shimada K, Hotta K, Kanehiro H, Konishi N, Yagita H, Nakajima Y (2009) Clinical importance of B7-H3 expression in human pancreatic cancer. Br J Cancer 101(10):1709–1716PubMedCrossRef

31.

Arigami T, Uenosono Y, Hirata M, Yanagita S, Ishigami S, Natsugoe S (2011) B7-H3 expression in gastric cancer: a novel molecular blood marker for detecting circulating tumor cells. Cancer Sci 102(5):1019–1024PubMedCrossRef

32.

Gregorio A, Corrias MV, Castriconi R, Dondero A, Mosconi M, Gambini C, Moretta A, Moretta L, Bottino C (2008) Small round blue cell tumours: diagnostic and prognostic usefulness of the expression of B7-H3 surface molecule. Histopathology 53(1):73–80PubMedCrossRef

33.

Zhang G, Xu Y, Lu X, Huang H, Zhou Y, Lu B, Zhang X (2009) Diagnosis value of serum B7-H3 expression in non-small cell lung cancer. Lung Cancer 66(2):245–249PubMedCrossRef

34.

Chavin G, Sheinin Y, Crispen PL, Boorjian SA, Roth TJ, Rangel L, Blute ML, Sebo TJ, Tindall DJ, Kwon ED, Karnes RJ (2009) Expression of immunosuppresive B7-H3 ligand by hormone-treated prostate cancer tumors and metastases. Clin Cancer Res 15(6):2174–2180PubMedCrossRef

35.

Xu H, Cheung IY, Guo HF, Cheung NK (2009) MicroRNA miR-29 modulates expression of immunoinhibitory molecule B7-H3: potential implications for immune based therapy of human solid tumors. Cancer Res 69(15):6275–6281PubMedCrossRef

36.

Xiong Y, Fang JH, Yun JP, Yang J, Zhang Y, Jia WH, Zhuang SM (2010) Effects of MicroRNA‐29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology 51(3):836–845PubMed

37.

Flavin R, Smyth P, Barrett C, Russell S, Wen H, Wei J, Laios A, O’Toole S, Ring M, Denning K, Li J, Aherne S, Sammarae D, Aziz NA, Alhadi A, Finn SP, Loda M, Sheils O, O’Leary JJ (2009) miR-29b expression is associated with disease-free survival in patients with ovarian serous carcinoma. Int J Gynecol Cancer 19(4):641–647PubMedCrossRef

38.

Sengupta S, den Boon JA, Chen I-H, Newton MA, Stanhope SA, Cheng Y-J, Chen C-J, Hildesheim A, Sugden B, Ahlquist P (2008) MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins. Proc Natl Acad Sci U S A 105(15):5874–5878PubMedCrossRef

39.

Garzon R, Heaphy CE, Havelange V, Fabbri M, Volinia S, Tsao T, Zanesi N, Kornblau SM, Marcucci G, Calin GA, Andreeff M, Croce CM (2009) MicroRNA 29b functions in acute myeloid leukemia. Blood 114(26):5331–5341PubMedCrossRef

Title: B7-H3 is expressed in human hepatocellular carcinoma and is associated with tumor aggressiveness and postoperative recurrence
Authors: Tai-Wei Sun
Qiang Gao
Shuang-Jian Qiu
Jian Zhou
Xiao-Ying Wang
Yong Yi
Jie-Yi Shi
Yong-Feng Xu
Ying-Hong Shi
Kang Song
Yong-Sheng Xiao
Jia Fan
Publication date: 01-11-2012
Publisher: Springer-Verlag
Published in: Cancer Immunology, Immunotherapy / Issue 11/2012
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-012-1278-5

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