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The expression, function, and clinical relevance of B7 family members in cancer

  • Focussed Research Review
  • Published:
Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

The modulation and suppression of anti-tumor immune responses is a characteristic feature of tumor cells to escape immune surveillance. Members of the B7 family are involved in this process, since the level of activation of the anti-tumor immune response depends on the balance between co-stimulatory and co-inhibitory signals. Some molecules are often overexpressed in tumors, which has been associated with the pathogenesis and progression of malignancies as well as their immunological and non-immunological functions. The B7 homologs play a key role in the maintenance of self-tolerance and the regulation of both innate and adaptive immunity in tumor-bearing hosts. Furthermore, the blockade of negative signals mediated by the interaction of co-inhibitory ligands and counter-receptors of the B7 family is currently being studied as a potential immunotherapeutic strategy for the treatment of cancer in humans.

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Abbreviations

ALL:

Acute lymphoblastic leukemia

BTLA:

B and T lymphocyte attenuator

CTL:

Cytotoxic T lymphocyte

CTLA4:

Cytotoxic T lymphocyte-associated antigen 4

CR:

Complete remission/response

CTL:

Cytotoxic T lymphocyte

HLA:

Human leukocyte antigen

ICOS:

Inducible co-stimulatory molecule

IFN:

Interferon

JAK:

Janus kinase

mAb:

Monoclonal antibody

MAPK:

Mitogen-activated protein kinase

MDS:

Myelodysplastic syndrome

MDSC:

Myeloid-derived suppressor cell

MHC:

Major histocompatibility complex

MZL:

Marginal zone lymphoma

NK:

Natural killer cell

NSCLC:

Non-small cell lung cancer

OR:

Objective response

PR:

Partial response

PTEN:

Phosphatase and tensin homolog

RCC:

Renal cell carcinoma

STAT:

Signal transducer and activator of transcription

T-ALL:

T cell lymphoblastic leukemia

TAM:

Tumor-associated macrophage

TCR:

T cell receptor

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

Treg:

Regulatory T cell

SD:

Stable disease

References

  1. Carreno BM, Collins M (2002) The B7 family of ligands and its receptors: new pathways for costimulation and inhibition of immune responses. Annu Rev Immunol 20:29–53

    Article  PubMed  CAS  Google Scholar 

  2. Yoshinaga SK, Whoriskey JS, Khare SD, Sarmiento U, Guo J, Horan T, Shih G, Zhang M, Coccia MA, Kohno T, Tafuri-Bladt A, Brankow D, Campbell P, Chang D, Chiu L, Dai T, Duncan G, Elliott GS, Hui A, McCabe SM, Scully S, Shahinian A, Shaklee CL, Van G, Mak TW, Senaldi G (1999) T-cell co-stimulation through B7RP-1 and ICOS. Nature 402(6763):827–832

    Article  PubMed  CAS  Google Scholar 

  3. 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(12):1365–1369

    Article  PubMed  CAS  Google Scholar 

  4. 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(3):261–268

    Article  PubMed  CAS  Google Scholar 

  5. Kaifu T, Escaliere B, Gastinel LN, Vivier E, Baratin M (2011) B7-H6/NKp30 interaction: a mechanism of alerting NK cells against tumors. Cell Mol Life Sci 68(21):3531–3539

    Article  PubMed  CAS  Google Scholar 

  6. Brandt CS, Baratin M, Yi EC, Kennedy J, Gao Z, Fox B, Haldeman B, Ostrander CD, Kaifu T, Chabannon C, Moretta A, West R, Xu W, Vivier E, Levin SD (2009) The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J Exp Med 206(7):1495–1503

    Article  PubMed  CAS  Google Scholar 

  7. 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):269–274

    Article  PubMed  CAS  Google Scholar 

  8. 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(6):849–861

    Article  PubMed  CAS  Google Scholar 

  9. Kroczek RA, Mages HW, Hutloff A (2004) Emerging paradigms of T-cell co-stimulation. Curr Opin Immunol 16(3):321–327

    Article  PubMed  CAS  Google Scholar 

  10. Jenkins MK, Johnson JG (1993) Molecules involved in T-cell costimulation. Curr Opin Immunol 5(3):361–367

    Article  PubMed  CAS  Google Scholar 

  11. Frauwirth KA, Thompson CB (2002) Activation and inhibition of lymphocytes by costimulation. J Clin Invest 109(3):295–299

    PubMed  CAS  Google Scholar 

  12. Hutloff A, Dittrich AM, Beier KC, Eljaschewitsch B, Kraft R, Anagnostopoulos I, Kroczek RA (1999) ICOS is an inducible T-cell co-stimulator structurally and functionally related to CD28. Nature 397(6716):263–266

    Article  PubMed  CAS  Google Scholar 

  13. Coyle AJ, Lehar S, Lloyd C, Tian J, Delaney T, Manning S, Nguyen T, Burwell T, Schneider H, Gonzalo JA, Gosselin M, Owen LR, Rudd CE, Gutierrez-Ramos JC (2000) The CD28-related molecule ICOS is required for effective T cell-dependent immune responses. Immunity 13(1):95–105

    Article  PubMed  CAS  Google Scholar 

  14. Yao S, Zhu Y, Zhu G, Augustine M, Zheng L, Goode DJ, Broadwater M, Ruff W, Flies S, Xu H, Flies D, Luo L, Wang S, Chen L (2011) B7-h2 is a costimulatory ligand for CD28 in human. Immunity 34(5):729–740

    Article  PubMed  CAS  Google Scholar 

  15. Pulko V, Harris KJ, Liu X, Gibbons RM, Harrington SM, Krco CJ, Kwon ED, Dong H (2011) B7-H1 expressed by activated CD8 T cells is essential for their survival. J Immunol 187(11):5606–5614

    Article  PubMed  CAS  Google Scholar 

  16. 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(8):793–800

    PubMed  CAS  Google Scholar 

  17. 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):899–906

    Article  PubMed  CAS  Google Scholar 

  18. 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):1754–1764

    Article  PubMed  CAS  Google Scholar 

  19. 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(9):4650–4654

    PubMed  CAS  Google Scholar 

  20. 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):871–881

    Article  PubMed  CAS  Google Scholar 

  21. Cheng C, Qu QX, Shen Y, Lv YT, Zhu YB, Zhang XG, Huang JA (2011) Overexpression of B7–H4 in tumor infiltrated dendritic cells. J Immunoassay Immunochem 32(4):353–364

    Article  PubMed  CAS  Google Scholar 

  22. Watanabe N, Gavrieli M, Sedy JR, Yang J, Fallarino F, Loftin SK, Hurchla MA, Zimmerman N, Sim J, Zang X, Murphy TL, Russell JH, Allison JP, Murphy KM (2003) BTLA is a lymphocyte inhibitory receptor with similarities to CTLA-4 and PD-1. Nat Immunol 4(7):670–679

    Article  PubMed  CAS  Google Scholar 

  23. Compaan DM, Gonzalez LC, Tom I, Loyet KM, Eaton D, Hymowitz SG (2005) Attenuating lymphocyte activity: the crystal structure of the BTLA–HVEM complex. J Biol Chem 280(47):39553–39561

    Article  PubMed  CAS  Google Scholar 

  24. Frigola X, Inman BA, Krco CJ, Liu X, Harrington SM, Bulur PA, Dietz AB, Dong H, Kwon ED (2012) Soluble B7–H1: differences in production between dendritic cells and T cells. Immunol Lett 142(1–2):78–82

    Article  PubMed  CAS  Google Scholar 

  25. Her M, Kim D, Oh M, Jeong H, Choi I (2009) Increased expression of soluble inducible costimulator ligand (ICOSL) in patients with systemic lupus erythematosus. Lupus 18(6):501–507

    Article  PubMed  CAS  Google Scholar 

  26. Luan Y, Ju J, Luo L, Zhang Z, Wang J, Zhu DM, Cheng L, Zhang SY, Chen L, Wang FS, Wang S (2012) Potential role of soluble B7–H3 in liver immunopathogenesis during chronic HBV infection. J Viral Hepat 19(1):23–31

    Article  PubMed  CAS  Google Scholar 

  27. Zhang G, Hou J, Shi J, Yu G, Lu B, Zhang X (2008) Soluble CD276 (B7–H3) is released from monocytes, dendritic cells and activated T cells and is detectable in normal human serum. Immunology 123(4):538–546

    Article  PubMed  CAS  Google Scholar 

  28. Azuma T, Zhu G, Xu H, Rietz AC, Drake CG, Matteson EL, Chen L (2009) Potential role of decoy B7–H4 in the pathogenesis of rheumatoid arthritis: a mouse model informed by clinical data. PLoS Med 6(10):e1000166

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  30. Ghebeh H, Tulbah A, Mohammed S, Elkum N, Bin Amer SM, Al-Tweigeri T, Dermime S (2007) Expression of B7–H1 in breast cancer patients is strongly associated with high proliferative Ki-67-expressing tumor cells. Int J Cancer 121(4):751–758

    Article  PubMed  CAS  Google Scholar 

  31. Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S (2007) Overexpression of B7–H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother 56(8):1173–1182

    Article  PubMed  CAS  Google Scholar 

  32. 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(15):5094–5100

    Article  PubMed  CAS  Google Scholar 

  33. Geng L, Huang D, Liu J, Qian Y, Deng J, Li D, Hu Z, Zhang J, Jiang G, Zheng S (2008) B7–H1 up-regulated expression in human pancreatic carcinoma tissue associates with tumor progression. J Cancer Res Clin Oncol 134(9):1021–1027

    Article  PubMed  CAS  Google Scholar 

  34. 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(1):19–24

    Article  PubMed  Google Scholar 

  35. Hino R, Kabashima K, Kato Y, Yagi H, Nakamura M, Honjo T, Okazaki T, Tokura Y (2010) Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 116(7):1757–1766

    Article  PubMed  Google Scholar 

  36. Ohigashi Y, Sho M, Yamada Y, Tsurui Y, Hamada K, Ikeda 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(8):2947–2953

    Article  PubMed  CAS  Google Scholar 

  37. Geng L, Deng J, Jiang G, Song P, Wang Z, Jiang Z, Zhang M, Zheng S (2011) B7-H1 up-regulated expression in human hepatocellular carcinoma tissue: correlation with tumor interleukin-10 levels. Hepatogastroenterology 58(107–108):960–964

    PubMed  CAS  Google Scholar 

  38. Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, Higuchi T, Yagi H, Takakura K, Minato N, Honjo T, Fujii S (2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD8 + T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 104(9):3360–3365

    Article  PubMed  CAS  Google Scholar 

  39. Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, Cachola KE, Murray JC, Tihan T, Jensen MC, Mischel PS, Stokoe D, Pieper RO (2007) Loss of tumor suppressor PTEN function increases B7–H1 expression and immunoresistance in glioma. Nat Med 13(1):84–88

    Article  PubMed  CAS  Google Scholar 

  40. Yao Y, Tao R, Wang X, Wang Y, Mao Y, Zhou LF (2009) B7–H1 is correlated with malignancy-grade gliomas but is not expressed exclusively on tumor stem-like cells. Neuro Oncol 11(6):757–766

    Article  PubMed  Google Scholar 

  41. 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(7):3381–3385

    Article  PubMed  CAS  Google Scholar 

  42. Yamamoto R, Nishikori M, Tashima M, Sakai T, Ichinohe T, Takaori-Kondo A, Ohmori K, Uchiyama T (2009) B7–H1 expression is regulated by MEK/ERK signaling pathway in anaplastic large cell lymphoma and Hodgkin lymphoma. Cancer Sci 100(11):2093–2100

    Article  PubMed  CAS  Google Scholar 

  43. Berthon C, Driss V, Liu J, Kuranda K, Leleu X, Jouy N, Hetuin D, Quesnel B (2010) In acute myeloid leukemia, B7–H1 (PD-L1) protection of blasts from cytotoxic T cells is induced by TLR ligands and interferon-gamma and can be reversed using MEK inhibitors. Cancer Immunol Immunother 59(12):1839–1849

    Article  PubMed  CAS  Google Scholar 

  44. Kondo A, Yamashita T, Tamura H, Zhao W, Tsuji T, Shimizu M, Shinya E, Takahashi H, Tamada K, Chen L, Dan K, Ogata K (2010) Interferon-gamma and tumor necrosis factor-alpha induce an immunoinhibitory molecule, B7–H1, via nuclear factor-kappaB activation in blasts in myelodysplastic syndromes. Blood 116(7):1124–1131

    Article  PubMed  CAS  Google Scholar 

  45. Tamura H, Dan K, Tamada K, Nakamura K, Shioi Y, Hyodo H, Wang SD, Dong H, Chen L, Ogata K (2005) Expression of functional B7-H2 and B7.2 costimulatory molecules and their prognostic implications in de novo acute myeloid leukemia. Clin Cancer Res 11(16):5708–5717

    Article  PubMed  CAS  Google Scholar 

  46. Loos M, Hedderich DM, Friess H, Kleeff J (2010) B7–h3 and its role in antitumor immunity. Clin Dev Immunol 2010:683875

    Article  PubMed  CAS  Google Scholar 

  47. 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):5150–5157

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  49. 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(2):143–151

    Article  PubMed  Google Scholar 

  50. 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(49):19458–19463

    Article  PubMed  CAS  Google Scholar 

  51. 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(1):44–52

    Article  PubMed  CAS  Google Scholar 

  52. Jiang J, Zhu Y, Wu C, Shen Y, Wei W, Chen L, Zheng X, Sun J, Lu B, Zhang X (2010) Tumor expression of B7–H4 predicts poor survival of patients suffering from gastric cancer. Cancer Immunol Immunother 59(11):1707–1714

    Article  PubMed  CAS  Google Scholar 

  53. Awadallah NS, Shroyer KR, Langer DA, Torkko KC, Chen YK, Bentz JS, Papkoff J, Liu W, Nash SR, Shah RJ (2008) Detection of B7–H4 and p53 in pancreatic cancer: potential role as a cytological diagnostic adjunct. Pancreas 36(2):200–206

    Article  PubMed  CAS  Google Scholar 

  54. 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(5):1842–1848

    Article  PubMed  CAS  Google Scholar 

  55. Chen LJ, Sun J, Wu HY, Zhou SM, Tan Y, Tan M, Shan BE, Lu BF, Zhang XG (2011) B7–H4 expression associates with cancer progression and predicts patient’s survival in human esophageal squamous cell carcinoma. Cancer Immunol Immunother 60(7):1047–1055

    Article  PubMed  CAS  Google Scholar 

  56. 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(27):10391–10396

    Article  PubMed  CAS  Google Scholar 

  57. Yao Y, Wang X, Jin K, Zhu J, Wang Y, Xiong S, Mao Y, Zhou L (2008) B7–H4 is preferentially expressed in non-dividing brain tumor cells and in a subset of brain tumor stem-like cells. J Neurooncol 89(2):121–129

    Article  PubMed  Google Scholar 

  58. Frigola X, Inman BA, Lohse CM, Krco CJ, Cheville JC, Thompson RH, Leibovich B, Blute ML, Dong H, Kwon ED (2011) Identification of a soluble form of B7–H1 that retains immunosuppressive activity and is associated with aggressive renal cell carcinoma. Clin Cancer Res 17(7):1915–1923

    Article  PubMed  CAS  Google Scholar 

  59. 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(15):6054–6058

    Article  PubMed  CAS  Google Scholar 

  60. 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):245–249

    Article  PubMed  Google Scholar 

  61. Simon I, Katsaros D, Rigault de la Longrais I, Massobrio M, Scorilas A, Kim NW, Sarno MJ, Wolfert RL, Diamandis EP (2007) B7–H4 is over-expressed in early-stage ovarian cancer and is independent of CA125 expression. Gynecol Oncol 106(2):334–341

    Article  PubMed  CAS  Google Scholar 

  62. Fu T, He Q, Sharma P (2011) The ICOS/ICOSL pathway is required for optimal antitumor responses mediated by anti-CTLA-4 therapy. Cancer Res 71(16):5445–5454

    Article  PubMed  CAS  Google Scholar 

  63. Mu CY, Huang JA, Chen Y, Chen C, Zhang XG (2011) High expression of PD-L1 in lung cancer may contribute to poor prognosis and tumor cells immune escape through suppressing tumor infiltrating dendritic cells maturation. Med Oncol 28(3):682–688

    Article  PubMed  CAS  Google Scholar 

  64. Wang L, Ma Q, Chen X, Guo K, Li J, Zhang M (2010) Clinical significance of B7–H1 and B7–1 expressions in pancreatic carcinoma. World J Surg 34(5):1059–1065

    Article  PubMed  Google Scholar 

  65. Thompson RH, Gillett MD, Cheville JC, Lohse CM, Dong H, Webster WS, Chen L, Zincke H, Blute ML, Leibovich BC, Kwon ED (2005) Costimulatory molecule B7–H1 in primary and metastatic clear cell renal cell carcinoma. Cancer 104(10):2084–2091

    Article  PubMed  CAS  Google Scholar 

  66. Gadiot J, Hooijkaas AI, Kaiser AD, van Tinteren H, van Boven H, Blank C (2011) Overall survival and PD-L1 expression in metastasized malignant melanoma. Cancer 117(10):2192–2201

    Article  PubMed  CAS  Google Scholar 

  67. Inman BA, Sebo TJ, Frigola X, Dong H, Bergstralh EJ, Frank I, Fradet Y, Lacombe L, Kwon ED (2007) PD-L1 (B7–H1) expression by urothelial carcinoma of the bladder and BCG-induced granulomata: associations with localized stage progression. Cancer 109(8):1499–1505

    Article  PubMed  CAS  Google Scholar 

  68. 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):457–459

    PubMed  CAS  Google Scholar 

  69. 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 9:463

    Article  PubMed  CAS  Google Scholar 

  70. 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):7893–7900

    Article  PubMed  CAS  Google Scholar 

  71. Brunner A, Hinterholzer S, Riss P, Heinze G, Brustmann H (2012) Immunoexpression of B7–H3 in endometrial cancer: relation to tumor T-cell infiltration and prognosis. Gynecol Oncol 124(1):105–111

    Article  PubMed  CAS  Google Scholar 

  72. He C, Qiao H, Jiang H, Sun X (2011) The inhibitory role of B7-h4 in antitumor immunity: association with cancer progression and survival. Clin Dev Immunol 2011:695834

    Article  PubMed  CAS  Google Scholar 

  73. Simon I, Zhuo S, Corral L, Diamandis EP, Sarno MJ, Wolfert RL, Kim NW (2006) B7–h4 is a novel membrane-bound protein and a candidate serum and tissue biomarker for ovarian cancer. Cancer Res 66(3):1570–1575

    Article  PubMed  CAS  Google Scholar 

  74. Sun T, Hu Z, Shen H, Lin D (2009) Genetic polymorphisms in cytotoxic T-lymphocyte antigen 4 and cancer: the dialectical nature of subtle human immune dysregulation. Cancer Res 69(15):6011–6014

    Article  PubMed  CAS  Google Scholar 

  75. Karabon L, Pawlak E, Tomkiewicz A, Jedynak A, Passowicz-Muszynska E, Zajda K, Jonkisz A, Jankowska R, Krzakowski M, Frydecka I (2011) CTLA-4, CD28, and ICOS gene polymorphism associations with non-small-cell lung cancer. Hum Immunol 72(10):947–954

    Article  PubMed  CAS  Google Scholar 

  76. Piras G, Monne M, Uras A, Palmas A, Murineddu M, Arru L, Bianchi A, Calvisi A, Curreli L, Gaviano E, Lai P, Murgia A, Latte GC, Noli A, Gabbas A (2005) Genetic analysis of the 2q33 region containing CD28-CTLA4-ICOS genes: association with non-Hodgkin’s lymphoma. Br J Haematol 129(6):784–790

    Article  PubMed  CAS  Google Scholar 

  77. 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(4):307–314

    Article  PubMed  CAS  Google Scholar 

  78. Han SJ, Ahn BJ, Waldron JS, Yang I, Fang S, Crane CA, Pieper RO, Parsa AT (2009) Gamma interferon-mediated superinduction of B7–H1 in PTEN-deficient glioblastoma: a paradoxical mechanism of immune evasion. NeuroReport 20(18):1597–1602

    Article  PubMed  CAS  Google Scholar 

  79. Crane CA, Panner A, Murray JC, Wilson SP, Xu H, Chen L, Simko JP, Waldman FM, Pieper RO, Parsa AT (2009) PI(3) kinase is associated with a mechanism of immunoresistance in breast and prostate cancer. Oncogene 28(2):306–312

    Article  PubMed  CAS  Google Scholar 

  80. Liu J, Hamrouni A, Wolowiec D, Coiteux V, Kuliczkowski K, Hetuin D, Saudemont A, Quesnel B (2007) Plasma cells from multiple myeloma patients express B7–H1 (PD-L1) and increase expression after stimulation with IFN-{gamma} and TLR ligands via a MyD88-, TRAF6-, and MEK-dependent pathway. Blood 110(1):296–304

    Article  PubMed  CAS  Google Scholar 

  81. Wasik MA, Zhang Q, Marzec M, Kasprzycka M, Wang HY, Liu X (2009) Anaplastic lymphoma kinase (ALK)-induced malignancies: novel mechanisms of cell transformation and potential therapeutic approaches. Semin Oncol 36(2 Suppl 1):S27–S35

    Article  PubMed  CAS  Google Scholar 

  82. Scandiuzzi L, Ghosh K, Zang X (2011) T cell costimulation and coinhibition: genetics and disease. Discov Med 12(63):119–128

    PubMed  Google Scholar 

  83. Yi KH, Chen L (2009) Fine tuning the immune response through B7–H3 and B7–H4. Immunol Rev 229(1):145–151

    Article  PubMed  CAS  Google Scholar 

  84. Marzec M, Zhang Q, Goradia A, Raghunath PN, Liu X, Paessler M, Wang HY, Wysocka M, Cheng M, Ruggeri BA, Wasik MA (2008) Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7–H1). Proc Natl Acad Sci USA 105(52):20852–20857

    Article  PubMed  CAS  Google Scholar 

  85. Steidl C, Shah SP, Woolcock BW, Rui L, Kawahara M, Farinha P, Johnson NA, Zhao Y, Telenius A, Neriah SB, McPherson A, Meissner B, Okoye UC, Diepstra A, van den Berg A, Sun M, Leung G, Jones SJ, Connors JM, Huntsman DG, Savage KJ, Rimsza LM, Horsman DE, Staudt LM, Steidl U, Marra MA, Gascoyne RD (2011) MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature 471(7338):377–381

    Article  PubMed  CAS  Google Scholar 

  86. Gong AY, Zhou R, Hu G, Li X, Splinter PL, O’Hara SP, LaRusso NF, Soukup GA, Dong H, Chen XM (2009) MicroRNA-513 regulates B7–H1 translation and is involved in IFN-gamma-induced B7–H1 expression in cholangiocytes. J Immunol 182(3):1325–1333

    PubMed  CAS  Google Scholar 

  87. 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):6275–6281

    Article  PubMed  CAS  Google Scholar 

  88. Fridman WH, Pages F, Sautes-Fridman C, Galon J (2012) The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer 12(4):298–306

    Article  PubMed  CAS  Google Scholar 

  89. Kaiser AD, Schuster K, Gadiot J, Borkner L, Daebritz H, Schmitt C, Andreesen R, Blank C (2012) Reduced tumor-antigen density leads to PD-1/PD-L1-mediated impairment of partially exhausted CD8(+) T cells. Eur J Immunol 42(3):662–671

    Article  PubMed  CAS  Google Scholar 

  90. Allavena P, Mantovani A (2012) Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment. Clin Exp Immunol 167(2):195–205

    Article  PubMed  CAS  Google Scholar 

  91. Chen J, Li G, Meng H, Fan Y, Song Y, Wang S, Zhu F, Guo C, Zhang L, Shi Y (2012) Upregulation of B7–H1 expression is associated with macrophage infiltration in hepatocellular carcinomas. Cancer Immunol Immunother 61(1):101–108

    Article  PubMed  CAS  Google Scholar 

  92. Filipazzi P, Huber V, Rivoltini L (2012) Phenotype, function and clinical implications of myeloid-derived suppressor cells in cancer patients. Cancer Immunol Immunother 61(2):255–263

    Article  PubMed  CAS  Google Scholar 

  93. Shin T, Yoshimura K, Crafton EB, Tsuchiya H, Housseau F, Koseki H, Schulick RD, Chen L, Pardoll DM (2005) In vivo costimulatory role of B7-DC in tuning T helper cell 1 and cytotoxic T lymphocyte responses. J Exp Med 201(10):1531–1541

    Article  PubMed  CAS  Google Scholar 

  94. Shin T, Kennedy G, Gorski K, Tsuchiya H, Koseki H, Azuma M, Yagita H, Chen L, Powell J, Pardoll D, Housseau F (2003) Cooperative B7–1/2 (CD80/CD86) and B7-DC costimulation of CD4+ T cells independent of the PD-1 receptor. J Exp Med 198(1):31–38

    Article  PubMed  CAS  Google Scholar 

  95. Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, Kurihara C, Kawaguchi A, Nagao S, Azuma M, Yagita H, Miura S (2009) Blockade of B7–H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. Int J Oncol 35(4):741–749

    PubMed  CAS  Google Scholar 

  96. Benson DM Jr, Bakan CE, Mishra A, Hofmeister CC, Efebera Y, Becknell B, Baiocchi RA, Zhang J, Yu J, Smith MK, Greenfield CN, Porcu P, Devine SM, Rotem-Yehudar R, Lozanski G, Byrd JC, Caligiuri MA (2010) The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 116(13):2286–2294

    Article  PubMed  CAS  Google Scholar 

  97. Zang X, Sullivan PS, Soslow RA, Waitz R, Reuter VE, Wilton A, Thaler HT, Arul M, Slovin SF, Wei J, Spriggs DR, Dupont J, Allison JP (2010) Tumor associated endothelial expression of B7–H3 predicts survival in ovarian carcinomas. Mod Pathol 23(8):1104–1112

    Article  PubMed  CAS  Google Scholar 

  98. 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(18):8900–8905

    Article  PubMed  CAS  Google Scholar 

  99. Cameron F, Whiteside G, Perry C (2011) Ipilimumab: first global approval. Drugs 71(8):1093–1104

    Article  PubMed  Google Scholar 

  100. Peggs KS, Quezada SA, Allison JP (2008) Cell intrinsic mechanisms of T-cell inhibition and application to cancer therapy. Immunol Rev 224:141–165

    Article  PubMed  CAS  Google Scholar 

  101. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R, Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J, Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbe C, Peschel C, Quirt I, Clark JI, Wolchok JD, Weber JS, Tian J, Yellin MJ, Nichol GM, Hoos A, Urba WJ (2010) Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 363(8):711–723

    Article  PubMed  CAS  Google Scholar 

  102. Small EJ, Tchekmedyian NS, Rini BI, Fong L, Lowy I, Allison JP (2007) A pilot trial of CTLA-4 blockade with human anti-CTLA-4 in patients with hormone-refractory prostate cancer. Clin Cancer Res 13(6):1810–1815

    Article  PubMed  CAS  Google Scholar 

  103. Yang JC, Beck KE, Blansfield JA, Tran KQ, Lowy I, Rosenberg SA (2005) Tumor regression in patients with metastatic renal cancer treated with a monoclonal antibody to CTLA4 (MDX-010). J Clin Oncol 2005 ASCO Annual meeting proceedings vol 23, no. 16S, Part I of II (June 1 Supplement), 2005: 2501

  104. Brahmer JR, Drake CG, Wollner I, Powderly JD, Picus J, Sharfman WH, Stankevich E, Pons A, Salay TM, McMiller TL, Gilson MM, Wang C, Selby M, Taube JM, Anders R, Chen L, Korman AJ, Pardoll DM, Lowy I, Topalian SL (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28(19):3167–3175

    Article  PubMed  CAS  Google Scholar 

  105. Sznol M (2011) Toxicity and activity of anti-PD-1 in phase 1 clinical trials. American association for cancer research (AACR) 102nd annual meeting. Orlando, FL; April 2–6

  106. McDermott DF Drake CG, Sznol M, Sosman JA, Smith DC, Powderly JD (2011) A phase I study to evalute safety and antitumor activity of biweekly BMS-936558 (Anti-PD-1, MDX-1106/ONO-4538) in patients with RCC and other advanced refractory malignancies (abstract). American Society for Clinical Oncology (ASCO) February 17–19, Orlando, FL. (J Clin Oncol 29:2011): (sippl 7; abstr. 331)

  107. Berger R, Rotem-Yehudar R, Slama G, Landes S, Kneller A, Leiba M, Koren-Michowitz M, Shimoni A, Nagler A (2008) Phase I safety and pharmacokinetic study of CT-011, a humanized antibody interacting with PD-1, in patients with advanced hematologic malignancies. Clin Cancer Res 14(10):3044–3051

    Article  PubMed  CAS  Google Scholar 

  108. Borkner L, Kaiser A, van de Kasteele W, Andreesen R, Mackensen A, Haanen JB, Schumacher TN, Blank C (2010) RNA interference targeting programmed death receptor-1 improves immune functions of tumor-specific T cells. Cancer Immunol Immunother 59(8):1173–1183

    Article  PubMed  CAS  Google Scholar 

  109. Chinnadurai R, Grakoui A (2010) B7–H4 mediates inhibition of T cell responses by activated murine hepatic stellate cells. Hepatology 52(6):2177–2185

    Article  PubMed  CAS  Google Scholar 

  110. Salceda S, Tang T, Kmet M, Munteanu A, Ghosh M, Macina R, Liu W, Pilkington G, Papkoff J (2005) The immunomodulatory protein B7–H4 is overexpressed in breast and ovarian cancers and promotes epithelial cell transformation. Exp Cell Res 306(1):128–141

    Article  PubMed  CAS  Google Scholar 

  111. Kaufman HL, Deraffele G, Mitcham J, Moroziewicz D, Cohen SM, Hurst-Wicker KS, Cheung K, Lee DS, Divito J, Voulo M, Donovan J, Dolan K, Manson K, Panicali D, Wang E, Horig H, Marincola FM (2005) Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma. J Clin Invest 115(7):1903–1912

    Article  PubMed  CAS  Google Scholar 

  112. Raez LE, Cassileth PA, Schlesselman JJ, Sridhar K, Padmanabhan S, Fisher EZ, Baldie PA, Podack ER (2004) Allogeneic vaccination with a B7.1 HLA-A gene-modified adenocarcinoma cell line in patients with advanced non-small-cell lung cancer. J Clin Oncol 22(14):2800–2807

    Article  PubMed  CAS  Google Scholar 

  113. Prieto PA, Yang JC, Sherry RM, Hughes MS, Kammula US, White DE, Levy CL, Rosenberg SA, Phan GQ (2012) CTLA-4 blockade with ipilimumab: long-term follow-up of 177 patients with metastatic melanoma. Clin Cancer Res 18(7):2039–2047

    Article  PubMed  CAS  Google Scholar 

  114. Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen L (2012) Colocalization of inflammatory response with b7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 4(127):127ra137

    Google Scholar 

  115. Sun J, Chen LJ, Zhang GB, Jiang JT, Zhu M, Tan Y, Wang HT, Lu BF, Zhang XG (2010) Clinical significance and regulation of the costimulatory molecule B7–H3 in human colorectal carcinoma. Cancer Immunol Immunother 59(8):1163–1171

    Article  PubMed  CAS  Google Scholar 

  116. Ghebeh H, Mohammed S, Al-Omair A, Qattan A, Lehe C, Al-Qudaihi G, Elkum N, Alshabanah M, Bin Amer S, Tulbah A, Ajarim D, Al-Tweigeri T, Dermime S (2006) The B7–H1 (PD-L1) T lymphocyte-inhibitory molecule is expressed in breast cancer patients with infiltrating ductal carcinoma: correlation with important high-risk prognostic factors. Neoplasia 8(3):190–198

    Article  PubMed  CAS  Google Scholar 

  117. 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(49):17174–17179

    Article  PubMed  CAS  Google Scholar 

  118. 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):1019–1024

    Article  PubMed  CAS  Google Scholar 

  119. Ribas A, Camacho LH, Lopez-Berestein G, Pavlov D, Bulanhagui CA, Millham R, Comin-Anduix B, Reuben JM, Seja E, Parker CA, Sharma A, Glaspy JA, Gomez-Navarro J (2005) Antitumor activity in melanoma and anti-self responses in a phase I trial with the anti-cytotoxic T lymphocyte-associated antigen 4 monoclonal antibody CP-675,206. J Clin Oncol 23(35):8968–8977

    Article  PubMed  CAS  Google Scholar 

  120. Hodi FS, Butler M, Oble DA, Seiden MV, Haluska FG, Kruse A, Macrae S, Nelson M, Canning C, Lowy I, Korman A, Lautz D, Russell S, Jaklitsch MT, Ramaiya N, Chen TC, Neuberg D, Allison JP, Mihm MC, Dranoff G (2008) Immunologic and clinical effects of antibody blockade of cytotoxic T lymphocyte-associated antigen 4 in previously vaccinated cancer patients. Proc Natl Acad Sci USA 105(8):3005–3010

    Article  PubMed  CAS  Google Scholar 

  121. Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, Davis T, Henry-Spires R, MacRae S, Willman A, Padera R, Jaklitsch MT, Shankar S, Chen TC, Korman A, Allison JP, Dranoff G (2003) Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci USA 100(8):4712–4717

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We would like to thank Sylvi Magdeburg for secretarial help and acknowledge the Wilhelm Roux Program of the Martin Luther University Halle-Wittenberg (D.Q.) and a grant from the Mildred Scheel Foundation, Bonn (B.S., D.Q.).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112, Halle (Saale), Germany

    Barbara Seliger & Dagmar Quandt

  2. Section of Rheumatology, Institute for Gastroenterology and Rheumatology, University of Leipzig, 04103, Leipzig, Germany

    Dagmar Quandt

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  1. Barbara Seliger
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Correspondence to Barbara Seliger.

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This paper is a Focussed Research Review based on a presentation given at the Eleventh International Conference on Progress in Vaccination against Cancer (PIVAC 11), held in Copenhagen, Denmark, 10–13 October 2011. It is part of a CII series of Focussed Research Reviews and meeting report.

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Seliger, B., Quandt, D. The expression, function, and clinical relevance of B7 family members in cancer. Cancer Immunol Immunother 61, 1327–1341 (2012). https://doi.org/10.1007/s00262-012-1293-6

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