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The B7 Family Member B7-H6: a New Bane of Tumor

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Pathology & Oncology Research

Abstract

B7-H6 is a ligand of NKp30, which is an activating receptor of natural killer (NK) cells. High expression of B7-H6 is found in certain types of tumor cells, such as lymphoma, leukemia and gastric carcinoma. The expression of B7-H6 can be induced by inflammatory stress in healthy cells. The expression of B7-H6 is significantly correlated with distant metastasis status and post-operative prognosis in cancer patients. The effectiveness of B7-H6 modified antitumor immunotherapy strategies had been verified in tumor-bearing mice, which opened a new door to targeted therapy. In this review, we will focus on the recent development on the roles of B7-H6 in tumor immunity, as well as mechanisms involved in the regulation of B7-H6 expression.

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References

  1. Pende D, Rivera P, Marcenaro S, Chang CC, Biassoni R, Conte R, Kubin M, Cosman D, Ferrone S, Moretta L, Moretta A (2002) Major histocompatibility complex class I-related chain a and UL16-binding protein expression on tumor cell lines of different histotypes: analysis of tumor susceptibility to NKG2D-dependent natural killer cell cytotoxicity. Cancer Res 62(21):6178–6186

    PubMed  CAS  Google Scholar 

  2. Pende D, Parolini S, Pessino A, Sivori S, Augugliaro R, Morelli L, Marcenaro E, Accame L, Malaspina A, Biassoni R, Bottino C, Moretta L, Moretta A (1999) Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J Exp Med 190(10):1505–1516

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Castriconi R, Dondero A, Augugliaro R, Cantoni C, Carnemolla B, Sementa AR, Negri F, Conte R, Corrias MV, Moretta L, Moretta A, Bottino C (2004) 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 U S A 101(34):12640–12645. https://doi.org/10.1073/pnas.0405025101

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Byrd A, Hoffmann SC, Jarahian M, Momburg F, Watzl C (2007) Expression analysis of the ligands for the natural killer cell receptors NKp30 and NKp44. PLoS One 2(12):e1339. https://doi.org/10.1371/journal.pone.0001339

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Biron CA, Nguyen KB, Pien GC, Cousens LP, Salazar-Mather TP (1999) Natural killer cells in antiviral defense: function and regulation by innate cytokines. Annu Rev Immunol 17:189–220. https://doi.org/10.1146/annurev.immunol.17.1.189

    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. https://doi.org/10.1084/jem.20090681

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Joyce MG, Tran P, Zhuravleva MA, Jaw J, Colonna M, Sun PD (2011) Crystal structure of human natural cytotoxicity receptor NKp30 and identification of its ligand binding site. Proc Natl Acad Sci U S A 108(15):6223–6228. https://doi.org/10.1073/pnas.1100622108

    Article  PubMed  PubMed Central  Google Scholar 

  8. Pogge von Strandmann E, Simhadri VR, von Tresckow B, Sasse S, Reiners KS, Hansen HP, Rothe A, Boll B, Simhadri VL, Borchmann P, McKinnon PJ, Hallek M, Engert A (2007) Human leukocyte antigen-B-associated transcript 3 is released from tumor cells and engages the NKp30 receptor on natural killer cells. Immunity 27(6):965–974. https://doi.org/10.1016/j.immuni.2007.10.010

    Article  PubMed  CAS  Google Scholar 

  9. Arnon TI, Achdout H, Levi O, Markel G, Saleh N, Katz G, Gazit R, Gonen-Gross T, Hanna J, Nahari E, Porgador A, Honigman A, Plachter B, Mevorach D, Wolf DG, Mandelboim O (2005) Inhibition of the NKp30 activating receptor by pp65 of human cytomegalovirus. Nat Immunol 6(5):515–523. https://doi.org/10.1038/ni1190

    Article  PubMed  CAS  Google Scholar 

  10. Simhadri VR, Reiners KS, Hansen HP, Topolar D, Simhadri VL, Nohroudi K, Kufer TA, Engert A, Pogge von Strandmann E (2008) Dendritic cells release HLA-B-associated transcript-3 positive exosomes to regulate natural killer function. PLoS One 3(10):e3377. https://doi.org/10.1371/journal.pone.0003377

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Mavoungou E, Held J, Mewono L, Kremsner PG (2007) A Duffy binding-like domain is involved in the NKp30-mediated recognition of plasmodium falciparum-parasitized erythrocytes by natural killer cells. J Infect Dis 195(10):1521–1531. https://doi.org/10.1086/515579

    Article  PubMed  CAS  Google Scholar 

  12. Hecht ML, Rosental B, Horlacher T, Hershkovitz O, De Paz JL, Noti C, Schauer S, Porgador A, Seeberger PH (2009) Natural cytotoxicity receptors NKp30, NKp44 and NKp46 bind to different heparan sulfate/heparin sequences. J Proteome Res 8(2):712–720. https://doi.org/10.1021/pr800747c

    Article  PubMed  CAS  Google Scholar 

  13. Li Y, Wang Q, Mariuzza RA (2011) Structure of the human activating natural cytotoxicity receptor NKp30 bound to its tumor cell ligand B7-H6. J Exp Med 208(4):703–714. https://doi.org/10.1084/jem.20102548

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Schlecker E, Fiegler N, Arnold A, Altevogt P, Rose-John S, Moldenhauer G, Sucker A, Paschen A, von Strandmann EP, Textor S, Cerwenka A (2014) Metalloprotease-mediated tumor cell shedding of B7-H6, the ligand of the natural killer cell-activating receptor NKp30. Cancer Res 74(13):3429–3440. https://doi.org/10.1158/0008-5472.CAN-13-3017

    Article  PubMed  CAS  Google Scholar 

  15. Salimi M, Xue L, Jolin H, Hardman C, Cousins DJ, McKenzie AN, Ogg GS (2016) Group 2 innate lymphoid cells express functional NKp30 receptor inducing type 2 cytokine production. J Immunol 196(1):45–54. https://doi.org/10.4049/jimmunol.1501102

    Article  PubMed  CAS  Google Scholar 

  16. Matta J, Baratin M, Chiche L, Forel JM, Cognet C, Thomas G, Farnarier C, Piperoglou C, Papazian L, Chaussabel D, Ugolini S, Vely F, Vivier E (2013) Induction of B7-H6, a ligand for the natural killer cell-activating receptor NKp30, in inflammatory conditions. Blood 122(3):394–404. https://doi.org/10.1182/blood-2013-01-481705

    Article  PubMed  CAS  Google Scholar 

  17. Chen XJ, Shen J, Zhang GB, Chen WC (2014) B7-H6 protein expression has no prognostic significance in human gastric carcinoma. Pathology oncology research : POR 20(1):203–207. https://doi.org/10.1007/s12253-013-9686-1

    Article  PubMed  CAS  Google Scholar 

  18. Zhang X, Zhang G, Qin Y, Bai R, Huang J (2014) B7-H6 expression in non-small cell lung cancers. Int J Clin Exp Pathol 7(10):6936–6942

    PubMed  PubMed Central  Google Scholar 

  19. Guo JG, Guo CC, He ZQ, Liu ZG, Wang Y, Mou YG (2016) Clinical significance of B7-H6 protein expression in astrocytoma. OncoTargets and therapy 9:3291–3297. https://doi.org/10.2147/OTT.S103771

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Pesce S, Tabellini G, Cantoni C, Patrizi O, Coltrini D, Rampinelli F, Matta J, Vivier E, Moretta A, Parolini S, Marcenaro E (2015) B7-H6-mediated downregulation of NKp30 in NK cells contributes to ovarian carcinoma immune escape. Oncoimmunology 4(4):e1001224. https://doi.org/10.1080/2162402X.2014.1001224

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  21. Zhou Y, Xu Y, Chen L, Xu B, Wu C, Jiang J (2015) B7-H6 expression correlates with cancer progression and patient's survival in human ovarian cancer. Int J Clin Exp Pathol 8(8):9428–9433

    PubMed  PubMed Central  CAS  Google Scholar 

  22. Xu Z, Shen J, Wang MH, Yi T, Yu Y, Zhu Y, Chen B, Chen J, Li L, Li M, Zuo J, Jiang H, Zhou D, Luan J, Xiao Z (2016) Comprehensive molecular profiling of the B7 family of immune-regulatory ligands in breast cancer. Oncoimmunology 5(8):e1207841. https://doi.org/10.1080/2162402X.2016.1207841

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Wu F, Wang J, Ke X (2016) Knockdown of B7-H6 inhibits tumor progression and enhances chemosensitivity in B-cell non-Hodgkin lymphoma. Int J Oncol 48(4):1561–1570. https://doi.org/10.3892/ijo.2016.3393

    Article  PubMed  CAS  Google Scholar 

  24. Gallinari P, Di Marco S, Jones P, Pallaoro M, Steinkuhler C (2007) HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics. Cell Res 17(3):195–211. https://doi.org/10.1038/sj.cr.7310149

    Article  PubMed  CAS  Google Scholar 

  25. Minucci S, Pelicci PG (2006) Histone deacetylase inhibitors and the promise of epigenetic (and more) treatments for cancer. Nat Rev Cancer 6(1):38–51. https://doi.org/10.1038/nrc1779

    Article  PubMed  CAS  Google Scholar 

  26. Witt O, Deubzer HE, Milde T, Oehme I (2009) HDAC family: what are the cancer relevant targets? Cancer Lett 277(1):8–21. https://doi.org/10.1016/j.canlet.2008.08.016

    Article  PubMed  CAS  Google Scholar 

  27. Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403(6765):41–45. https://doi.org/10.1038/47412

    Article  PubMed  CAS  Google Scholar 

  28. Fiegler N, Textor S, Arnold A, Rolle A, Oehme I, Breuhahn K, Moldenhauer G, Witzens-Harig M, Cerwenka A (2013) Downregulation of the activating NKp30 ligand B7-H6 by HDAC inhibitors impairs tumor cell recognition by NK cells. Blood 122(5):684–693. https://doi.org/10.1182/blood-2013-02-482513

    Article  PubMed  CAS  Google Scholar 

  29. Wu E, Croucher PI, McKie N (1997) Expression of members of the novel membrane linked metalloproteinase family ADAM in cells derived from a range of haematological malignancies. Biochem Biophys Res Commun 235(2):437–442. https://doi.org/10.1006/bbrc.1997.6714

    Article  PubMed  CAS  Google Scholar 

  30. Ohta S, Harigai M, Tanaka M, Kawaguchi Y, Sugiura T, Takagi K, Fukasawa C, Hara M, Kamatani N (2001) Tumor necrosis factor-alpha (TNF-alpha) converting enzyme contributes to production of TNF-alpha in synovial tissues from patients with rheumatoid arthritis. J Rheumatol 28(8):1756–1763

    PubMed  CAS  Google Scholar 

  31. Horiuchi K, Kimura T, Miyamoto T, Takaishi H, Okada Y, Toyama Y, Blobel CP (2007) Cutting edge: TNF-alpha-converting enzyme (TACE/ADAM17) inactivation in mouse myeloid cells prevents lethality from endotoxin shock. J Immunol 179(5):2686–2689

    Article  PubMed  CAS  Google Scholar 

  32. Ding X, Yang LY, Huang GW, Wang W, WQ L (2004) ADAM17 mRNA expression and pathological features of hepatocellular carcinoma. World J Gastroenterol 10(18):2735–2739

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Cesaro A, Abakar-Mahamat A, Brest P, Lassalle S, Selva E, Filippi J, Hebuterne X, Hugot JP, Doglio A, Galland F, Naquet P, Vouret-Craviari V, Mograbi B, Hofman PM (2009) Differential expression and regulation of ADAM17 and TIMP3 in acute inflamed intestinal epithelia. Am J Physiol Gastrointest Liver Physiol 296(6):G1332–G1343. https://doi.org/10.1152/ajpgi.90641.2008

    Article  PubMed  CAS  Google Scholar 

  34. Lendeckel U, Kohl J, Arndt M, Carl-McGrath S, Donat H, Rocken C (2005) Increased expression of ADAM family members in human breast cancer and breast cancer cell lines. J Cancer Res Clin Oncol 131(1):41–48. https://doi.org/10.1007/s00432-004-0619-y

    Article  PubMed  CAS  Google Scholar 

  35. McGowan PM, McKiernan E, Bolster F, Ryan BM, Hill AD, McDermott EW, Evoy D, O'Higgins N, Crown J, Duffy MJ (2008) ADAM-17 predicts adverse outcome in patients with breast cancer. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO 19(6):1075–1081. https://doi.org/10.1093/annonc/mdm609

    Article  CAS  Google Scholar 

  36. Lee SB, Schramme A, Doberstein K, Dummer R, Abdel-Bakky MS, Keller S, Altevogt P, ST O, Reichrath J, Oxmann D, Pfeilschifter J, Mihic-Probst D, Gutwein P (2010) ADAM10 is upregulated in melanoma metastasis compared with primary melanoma. Journal Invest Dermatol 130(3):763–773. https://doi.org/10.1038/jid.2009.335

    Article  CAS  Google Scholar 

  37. Saftig P, Reiss K (2011) The "a Disintegrin and Metalloproteases" ADAM10 and ADAM17: novel drug targets with therapeutic potential? Eur J Cell Biol 90(6–7):527–535. https://doi.org/10.1016/j.ejcb.2010.11.005

    Article  PubMed  CAS  Google Scholar 

  38. Semeraro M, Rusakiewicz S, Zitvogel L, Kroemer G (2015) Natural killer cell mediated immunosurveillance of pediatric neuroblastoma. Oncoimmunology 4(11):e1042202. https://doi.org/10.1080/2162402X.2015.1042202

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Textor S, Bossler F, Henrich KO, Gartlgruber M, Pollmann J, Fiegler N, Arnold A, Westermann F, Waldburger N, Breuhahn K, Golfier S, Witzens-Harig M, Cerwenka A (2016) The proto-oncogene Myc drives expression of the NK cell-activating NKp30 ligand B7-H6 in tumor cells. Oncoimmunology 5(7):e1116674. https://doi.org/10.1080/2162402X.2015.1116674

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Semeraro M, Rusakiewicz S, Minard-Colin V, Delahaye NF, Enot D, Vely F, Marabelle A, Papoular B, Piperoglou C, Ponzoni M, Perri P, Tchirkov A, Matta J, Lapierre V, Shekarian T, Valsesia-Wittmann S, Commo F, Prada N, Poirier-Colame V, Bressac B, Cotteret S, Brugieres L, Farace F, Chaput N, Kroemer G, Valteau-Couanet D, Zitvogel L (2015) Clinical impact of the NKp30/B7-H6 axis in high-risk neuroblastoma patients. Sci Transl Med 7(283):283ra255. https://doi.org/10.1126/scitranslmed.aaa2327

    Article  CAS  Google Scholar 

  41. Kellner C, Maurer T, Hallack D, Repp R, van de Winkel JG, Parren PW, Valerius T, Humpe A, Gramatzki M, Peipp M (2012) Mimicking an induced self phenotype by coating lymphomas with the NKp30 ligand B7-H6 promotes NK cell cytotoxicity. J Immunol 189(10):5037–5046. https://doi.org/10.4049/jimmunol.1201321

    Article  PubMed  CAS  Google Scholar 

  42. Zhang T, MR W, Sentman CL (2012) An NKp30-based chimeric antigen receptor promotes T cell effector functions and antitumor efficacy in vivo. J Immunol 189(5):2290–2299. https://doi.org/10.4049/jimmunol.1103495

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. MR W, Zhang T, Gacerez AT, Coupet TA, DeMars LR, Sentman CL (2015) B7H6-specific Bispecific T cell engagers lead to tumor elimination and host antitumor immunity. J Immunol 194(11):5305–5311. https://doi.org/10.4049/jimmunol.1402517

    Article  CAS  Google Scholar 

  44. Xu X, Narni-Mancinelli E, Cantoni C, Li Y, Guia S, Gauthier L, Chen Q, Moretta A, Vely F, Eisenstein E, Rangarajan S, Vivier E, Mariuzza RA (2016) Structural insights into the inhibitory mechanism of an antibody against B7-H6, a stress-induced cellular ligand for the natural killer cell receptor NKp30. J Mol Biol 428(22):4457–4466. https://doi.org/10.1016/j.jmb.2016.09.011

    Article  PubMed  CAS  Google Scholar 

  45. Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C (2002) Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 195(3):343–351

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Vitale M, Della Chiesa M, Carlomagno S, Pende D, Arico M, Moretta L, Moretta A (2005) NK-dependent DC maturation is mediated by TNFalpha and IFNgamma released upon engagement of the NKp30 triggering receptor. Blood 106(2):566–571. https://doi.org/10.1182/blood-2004-10-4035

    Article  PubMed  CAS  Google Scholar 

  47. Delahaye NF, Rusakiewicz S, Martins I, Menard C, Roux S, Lyonnet L, Paul P, Sarabi M, Chaput N, Semeraro M, Minard-Colin V, Poirier-Colame V, Chaba K, Flament C, Baud V, Authier H, Kerdine-Romer S, Pallardy M, Cremer I, Peaudecerf L, Rocha B, Valteau-Couanet D, Gutierrez JC, Nunes JA, Commo F, Bonvalot S, Ibrahim N, Terrier P, Opolon P, Bottino C, Moretta A, Tavernier J, Rihet P, Coindre JM, Blay JY, Isambert N, Emile JF, Vivier E, Lecesne A, Kroemer G, Zitvogel L (2011) Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat Med 17(6):700–707. https://doi.org/10.1038/nm.2366

    Article  PubMed  CAS  Google Scholar 

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Funding

This study was supported by Priority Academic Program Development of Jiangsu Higher Education Institutions.

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Authors and Affiliations

  1. Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China

    Ying Chen, Xi Jia & Yang He

  2. Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China

    Jun Mo

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  1. Ying Chen
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Correspondence to Yang He.

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Chen, Y., Mo, J., Jia, X. et al. The B7 Family Member B7-H6: a New Bane of Tumor. Pathol. Oncol. Res. 24, 717–721 (2018). https://doi.org/10.1007/s12253-017-0357-5

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