Springer Seminars in Immunopathology

, Volume 28, Issue 4, pp 321–328 | Cite as

Fc gamma receptors and cancer

  • Lydie Cassard
  • Joël Cohen-Solal
  • Sophie Camilleri-Broët
  • Emilie Fournier
  • Wolf Herman Fridman
  • Catherine Sautès-Fridman
Review
First Online:
Received:
Accepted:

Abstract

FcγRs are a family of heterogeneous molecules that play opposite roles in immune response and control the effector functions of IgG antibodies. In many cancers, IgG antibodies are produced that recognize cancer cells, form immune complexes and therefore, activate FcγR. The therapeutic efficacy of monoclonal IgG antibodies against hematopoietic and epithelial tumors also argue for an important role of IgG antibodies in anti-tumor defenses. Since the 1980s, a series of lines of evidence in experimental models and in humans strongly suggest that FcγR are involved in the therapeutic activity of monoclonal IgG antibodies by activating the cytotoxic activity of FcγR-positive cells such as NK cells, monocytes, macrophages and neutrophils and by increasing antigen presentation by dendritic cells. Since many cell types co-express activating and inhibitory FcγR, the FcγR-dependent effector functions of IgG anti-tumor antibodies are counterbalanced by the inhibitory FcγRIIB. In addition, some tumor cells express FcγR either constitutively, such as B cell lymphomas or ectopically, such as 40% of human metastatic melanoma. The tumor FcγR isoform is preferentially FcγRIIB, which is functional at least in human metastatic melanoma. This review summarizes these data and discusses how FcγRIIB expression may influence the anti-tumor immune reaction and how beneficial or deleterious this expression could be for the efficiency of therapeutics based on monoclonal anti-tumor antibodies.

Keywords

Melanoma B cell lymphoma Prognostic value Antibody therapy Anti-tumor immunity 
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Notes

Acknowledgments

We thank T. Dorval, X. Sastre-Garrau, C. Mathiot, P. Broët, A. Delmer, J. Diebold, T. J. Molina and the GELA for their contributions in the studies described herein. Financial support was given by the Association pour la Recherche contre le Cancer (ARC-ARECA) and the Institut National de la Santé et de la Recherche Medicale (INSERM).

References

  1. 1.
    Hulett MD, Hogarth PM (1994) Molecular basis of Fc receptor function. Adv Immunol 57:1–127PubMedGoogle Scholar
  2. 2.
    Fridman WH, Bonnerot C, Daeron M, Amigorena S, Teillaud JL, Sautes C (1992) Structural bases of Fc gamma receptor functions. Immunol Rev 125:49–76PubMedCrossRefGoogle Scholar
  3. 3.
    Takai T (2005) Fc receptors and their role in immune regulation and autoimmunity. J Clin Immunol 25:1–18PubMedCrossRefGoogle Scholar
  4. 4.
    Deo YM, Graziano RF, Repp R, van de Winkel JG (1997) Clinical significance of IgG Fc receptors and Fc gamma R-directed immunotherapies. Immunol Today 18:127–135PubMedCrossRefGoogle Scholar
  5. 5.
    Amigorena S, Bonnerot C, Drake JR, Choquet D, Hunziker W, Guillet JG, Webster P, Sautes C, Mellman I, Fridman WH (1992) Cytoplasmic domain heterogeneity and functions of IgG Fc receptors in B lymphocytes. Science 256:1808–1812PubMedCrossRefGoogle Scholar
  6. 6.
    Van den Herik-Oudijk IE, Capel PJ, van der Bruggen T, van de Winkel JG (1995) Identification of signaling motifs within human Fc gamma RIIa and Fc gamma RIIb isoforms. Blood 85:2202–2211PubMedGoogle Scholar
  7. 7.
    Daeron M (1997) Fc receptor biology. Annu Rev Immunol 15:203–234PubMedCrossRefGoogle Scholar
  8. 8.
    Sarmay G, Koncz G, Gergely J (1996) Integration of activatory and inhibitory signals in human B-cells. Immunol Lett 54:93–100PubMedCrossRefGoogle Scholar
  9. 9.
    Isnardi I, Bruhns P, Bismuth G, Fridman WH, Daeron M (2006) The SH2 domain-containing inositol 5-phosphatase SHIP1 is recruited to the intracytoplasmic domain of human FcgammaRIIB and is mandatory for negative regulation of B cell activation. Immunol Lett 104:156–165PubMedCrossRefGoogle Scholar
  10. 10.
    Sahin U, Tureci O, Schmitt H, Cochlovius B, Johannes T, Schmits R, Stenner F, Luo G, Schobert I, Pfreundschuh M (1995) Human neoplasms elicit multiple specific immune responses in the autologous host. Proc Natl Acad Sci U S A 92:11810–11813PubMedCrossRefGoogle Scholar
  11. 11.
    Jager E, Chen YT, Drijfhout JW, Karbach J, Ringhoffer M, Jager D, Arand M, Wada H, Noguchi Y, Stockert E, Old LJ, Knuth A (1998) Simultaneous humoral and cellular immune response against cancer–testis antigen NY-ESO-1: definition of human histocompatibility leukocyte antigen (HLA)-A2-binding peptide epitopes. J Exp Med 187:265–270PubMedCrossRefGoogle Scholar
  12. 12.
    Lake DF, Huynh WC, Hersh EM (2000) Natural and induced human antibody response to cancer. Cancer Invest 18:480–489PubMedGoogle Scholar
  13. 13.
    Ragupathi G, Meyers M, Adluri S, Howard L, Musselli C, Livingston PO (2000) Induction of antibodies against GD3 ganglioside in melanoma patients by vaccination with GD3-lactone-KLH conjugate plus immunological adjuvant QS-21. Int J Cancer 85:659–666PubMedCrossRefGoogle Scholar
  14. 14.
    Lutzky J, Gonzalez-Angulo AM, Orzano JA (2002) Antibody-based vaccines for the treatment of melanoma. Semin Oncol 29:462–470PubMedCrossRefGoogle Scholar
  15. 15.
    Ehlken H, Schadendorf D, Eichmuller S (2004) Humoral immune response against melanoma antigens induced by vaccination with cytokine gene-modified autologous tumor cells. Int J Cancer 108:307–313PubMedCrossRefGoogle Scholar
  16. 16.
    White CA, Weaver RL, Grillo-Lopez AJ (2001) Antibody-targeted immunotherapy for treatment of malignancy. Annu Rev Med 52:125–145PubMedCrossRefGoogle Scholar
  17. 17.
    Carter PJ (2006) Potent antibody therapeutics by design. Nat Rev Immunol 6:343–357PubMedCrossRefGoogle Scholar
  18. 18.
    Akiyama K, Ebihara S, Yada A, Matsumura K, Aiba S, Nukiwa T, Takai T (2003) Targeting apoptotic tumor cells to Fc gamma R provides efficient and versatile vaccination against tumors by dendritic cells. J Immunol 170:1641–1648PubMedGoogle Scholar
  19. 19.
    Rafiq K, Bergtold A, Clynes R (2002) Immune complex-mediated antigen presentation induces tumor immunity. J Clin Invest 110:71–79PubMedCrossRefGoogle Scholar
  20. 20.
    Adams DO, Hall T, Steplewski Z, Koprowski H (1984) Tumors undergoing rejection induced by monoclonal antibodies of the IgG2a isotype contain increased numbers of macrophages activated for a distinctive form of antibody-dependent cytolysis. Proc Natl Acad Sci U S A 81:3506–3510PubMedCrossRefGoogle Scholar
  21. 21.
    Denkers EY, Badger CC, Ledbetter JA, Bernstein ID (1985) Influence of antibody isotype on passive serotherapy of lymphoma. J Immunol 135:2183–2186PubMedGoogle Scholar
  22. 22.
    Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenberg J, Grillo-Lopez A, Levy R (1994) Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 84:2457–2466PubMedGoogle Scholar
  23. 23.
    Dyer MJ, Hale G, Hayhoe FG, Waldmann H (1989) Effects of CAMPATH-1 antibodies in vivo in patients with lymphoid malignancies: influence of antibody isotype. Blood 73:1431–1439PubMedGoogle Scholar
  24. 24.
    Clynes R, Takechi Y, Moroi Y, Houghton A, Ravetch JV (1998) Fc receptors are required in passive and active immunity to melanoma. Proc Natl Acad Sci U S A 95:652–656PubMedCrossRefGoogle Scholar
  25. 25.
    Bevaart L, Jansen MJ, van Vugt MJ, Verbeek JS, van de Winkel JG, Leusen JH (2006) The high-affinity IgG receptor, FcgammaRI, plays a central role in antibody therapy of experimental melanoma. Cancer Res 66:1261–1264PubMedCrossRefGoogle Scholar
  26. 26.
    Nimmerjahn F, Ravetch JV (2005) Divergent immunoglobulin g subclass activity through selective Fc receptor binding. Science 310:1510–1512PubMedCrossRefGoogle Scholar
  27. 27.
    Nimmerjahn F, Ravetch JV (2006) Fcgamma receptors: old friends and new family members. Immunity 24:19–28PubMedCrossRefGoogle Scholar
  28. 28.
    Cartron G, Dacheux L, Salles G, Solal-Celigny P, Bardos P, Colombat P, Watier H (2002) Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood 99:754–758PubMedCrossRefGoogle Scholar
  29. 29.
    Clynes RA, Towers TL, Presta LG, Ravetch JV (2000) Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 6:443–446PubMedCrossRefGoogle Scholar
  30. 30.
    van Spriel AB, van Ojik HH, van de Winkel JG (2000) Immunotherapeutic perspective for bispecific antibodies. Immunol Today 21:391–397PubMedCrossRefGoogle Scholar
  31. 31.
    Berends D, van der Kwast TH, de Both NJ, Mulder PG (1989) Factors influencing antibody-mediated cytotoxicity during the immunotherapy of Rauscher-virus-induced myeloid leukemic cells. Cancer Immunol Immunother 28:123–130PubMedCrossRefGoogle Scholar
  32. 32.
    van Spriel AB, van Ojik HH, Bakker A, Jansen MJ, van de Winkel JG (2003) Mac-1 (CD11b/CD18) is crucial for effective Fc receptor-mediated immunity to melanoma. Blood 101:253–258PubMedCrossRefGoogle Scholar
  33. 33.
    Sedmak DD, Davis DH, Singh U, van de Winkel JG, Anderson CL (1991) Expression of IgG Fc receptor antigens in placenta and on endothelial cells in humans. An immunohistochemical study. Am J Pathol 138:175–181PubMedGoogle Scholar
  34. 34.
    Lyden TW, Robinson JM, Tridandapani S, Teillaud JL, Garber SA, Osborne JM, Frey J, Budde P, Anderson CL (2001) The Fc receptor for IgG expressed in the villus endothelium of human placenta is Fc gamma RIIb2. J Immunol 166:3882–3889PubMedGoogle Scholar
  35. 35.
    Hussain LA, Kelly CG, Hecht EM, Fellowes R, Jourdan M, Lehner T (1991) The expression of Fc receptors for immunoglobulin G in human rectal epithelium. AIDS 5:1089–1094PubMedCrossRefGoogle Scholar
  36. 36.
    Estienne V, Duthoit C, Reichert M, Praetor A, Carayon P, Hunziker W, Ruf J (2002) Androgen-dependent expression of FcgammaRIIB2 by thyrocytes from patients with autoimmune Graves’ disease: a possible molecular clue for sex dependence of autoimmune disease. FASEB J 16:1087–1092PubMedCrossRefGoogle Scholar
  37. 37.
    Milgrom F, Humphrey LJ, Tonder O, Yasuda J, Witebsky E (1968) Antibody-mediated hemadsorption by tumor tissues. Int Arch Allergy Appl Immunol 33:478–492PubMedGoogle Scholar
  38. 38.
    Tonder O, Thunold S (1973) Receptors for immunoglobulin Fc in human malignant tissues. Scand J Immunol 2:207–215PubMedCrossRefGoogle Scholar
  39. 39.
    Witz IP (1973) The biological significance of tumor-bound immunoglobulins. Curr Top Microbiol Immunol 61:151–171PubMedGoogle Scholar
  40. 40.
    Biran H, Mavligit GM, Moake JL (1979) Receptor sites for complement and for immune complexes on human nonhemopoietic tumor cells. Cancer 44:131–135PubMedCrossRefGoogle Scholar
  41. 41.
    Noltenius HW (1981) Fc and complement receptors on malignant tumor cells. Cancer 48:1761–1767PubMedCrossRefGoogle Scholar
  42. 42.
    Braslawsky GR, Serban D, Witz IP (1976) Receptors for immune complexes on cells within a polyoma virus-induced murine sarcoma. Eur J Immunol 6:579–583PubMedGoogle Scholar
  43. 43.
    Svennevig JL, Andersson TR (1982) Cells bearing Fc receptors in human malignant solid tumours. Br J Cancer 45:201–208PubMedGoogle Scholar
  44. 44.
    Ran M, Teillaud JL, Fridman WH, Frenkel H, Halachmi E, Katz B, Gips M, Shlomo Y, Barzilay J, Witz IP (1988) Increased expression of Fc gamma receptor in cancer patients and tumor bearing mice. Mol Immunol 25:1159–1167PubMedCrossRefGoogle Scholar
  45. 45.
    Ran M, Katz B, Kimchi N, Halachmi E, Teillaud JL, Even J, Berko-Flint Y, Atlas E, Fridman WH, Witz IP (1991) In vivo acquisition of Fc gamma RII expression on polyoma virus-transformed cells derived from tumors of long latency. Cancer Res 51:612–618PubMedGoogle Scholar
  46. 46.
    Szymaniec S, James K (1976) Studies on the Fc receptor bearing cells in a transplanted methylcholanthrene induced mouse fibrosarcoma. Br J Cancer 33:36–50PubMedGoogle Scholar
  47. 47.
    Gorini G, Ciotti MT, Starace G, Vigneti E, Raschella G (1992) Fc gamma receptors are expressed on human neuroblastoma cell lines: lack of correlation with N-myc oncogene activity. Int J Neurosci 62:287–297PubMedGoogle Scholar
  48. 48.
    Cassard L, Cohen-Solal JF, Galinha A, Sastre-Garau X, Mathiot C, Galon J, Dorval T, Bernheim A, Fridman WH, Sautes-Fridman C (2002) Modulation of tumor growth by inhibitory Fc(gamma) receptor expressed by human melanoma cells. J Clin Invest 110:1549–1557PubMedCrossRefGoogle Scholar
  49. 49.
    Neauport-Sautes C, Daeron M, Teillaud JL, Blank U, Fridman WH (1986) The occurrence, structural and functional properties of immunoglobulin Fc receptors on murine neoplastic cells. Int Rev Immunol 1:237–271PubMedGoogle Scholar
  50. 50.
    Tridandapani S, Siefker K, Teillaud JL, Carter JE, Wewers MD, Anderson CL (2002) Regulated expression and inhibitory function of Fcgamma RIIb in human monocytic cells. J Biol Chem 277:5082–5089PubMedCrossRefGoogle Scholar
  51. 51.
    Langer AB, Emmanuel N, Even J, Fridman WH, Gohar O, Gonen B, Katz BZ, Ran M, Smorodinsky NI, Witz IP (1992) Phenotypic properties of 3T3 cells transformed in vitro with polyoma virus and passaged once in syngeneic animals. Immunobiology 185:281–291PubMedGoogle Scholar
  52. 52.
    Zusman T, Lisansky E, Arons E, Anavi R, Bonnerot C, Sautes C, Fridman WH, Witz IP, Ran M (1996) Contribution of the intracellular domain of murine Fc-gamma receptor type IIB1 to its tumor-enhancing potential. Int J Cancer 68:219–227PubMedCrossRefGoogle Scholar
  53. 53.
    Witz IP, Ran M (1992) FcR may function as a progression factor of nonlymphoid tumors. Immunol Res 11:283–295PubMedCrossRefGoogle Scholar
  54. 54.
    Azeredo da Silveira S, Kikuchi S, Fossati-Jimack L, Moll T, Saito T, Verbeek JS, Botto M, Walport MJ, Carroll M, Izui S (2002) Complement activation selectively potentiates the pathogenicity of the IgG2b and IgG3 isotypes of a high affinity anti-erythrocyte autoantibody. J Exp Med 195:665–672PubMedCrossRefGoogle Scholar
  55. 55.
    Camilleri-Broet S, Cassard L, Broet P, Delmer A, Le Touneau A, Diebold J, Fridman WH, Molina TJ, Sautes-Fridman C (2004) FcgammaRIIB is differentially expressed during B cell maturation and in B-cell lymphomas. Br J Haematol 124:55–62PubMedCrossRefGoogle Scholar
  56. 56.
    Rao SP, Vora KA, Manser T (2002) Differential expression of the inhibitory IgG Fc receptor FcgammaRIIB on germinal center cells: implications for selection of high-affinity B cells. J Immunol 169:1859–1868PubMedGoogle Scholar
  57. 57.
    Pulford K, Ralfkiaer E, MacDonald SM, Erber WN, Falini B, Gatter KC, Mason DY (1986) A new monoclonal antibody (KB61) recognizing a novel antigen which is selectively expressed on a subpopulation of human B lymphocytes. Immunology 57:71–76PubMedGoogle Scholar
  58. 58.
    Macardle PJ, Mardell C, Bailey S, Wheatland L, Ho A, Jessup C, Roberton DM, Zola H (2002) FcgammaRIIb expression on human germinal center B lymphocytes. Eur J Immunol 32:3736–3744PubMedCrossRefGoogle Scholar
  59. 59.
    Pearse RN, Kawabe T, Bolland S, Guinamard R, Kurosaki T, Ravetch JV (1999) SHIP recruitment attenuates Fc gamma RIIB-induced B cell apoptosis. Immunity 10:753–760PubMedCrossRefGoogle Scholar
  60. 60.
    Itoyama T, Nanjungud G, Chen W, Dyomin VG, Teruya-Feldstein J, Jhanwar SC, Zelenetz AD, Chaganti RS (2002) Molecular cytogenetic analysis of genomic instability at the 1q12–22 chromosomal site in B-cell non-Hodgkin lymphoma. Genes Chromosomes Cancer 35:318–328PubMedCrossRefGoogle Scholar
  61. 61.
    Callanan MB, Le Baccon P, Mossuz P, Duley S, Bastard C, Hamoudi R, Dyer MJ, Klobeck G, Rimokh R, Sotto JJ, Leroux D (2000) The IgG Fc receptor, FcgammaRIIB, is a target for deregulation by chromosomal translocation in malignant lymphoma. Proc Natl Acad Sci U S A 97:309–314PubMedCrossRefGoogle Scholar
  62. 62.
    Chen W, Palanisamy N, Schmidt H, Teruya-Feldstein J, Jhanwar SC, Zelenetz AD, Houldsworth J, Chaganti RS (2001) Deregulation of FCGR2B expression by 1q21 rearrangements in follicular lymphomas. Oncogene 20:7686–7693PubMedCrossRefGoogle Scholar
  63. 63.
    Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson Jr J, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Levy R, Wilson W, Grever MR, Byrd JC, Botstein D, Brown PO, Staudt LM (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503–511PubMedCrossRefGoogle Scholar
  64. 64.
    Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346:235–242PubMedCrossRefGoogle Scholar
  65. 65.
    Camilleri-Broet S, Mounier N, Delmer A, Briere J, Casasnovas O, Cassard L, Gaulard P, Christian B, Coiffier B, Sautes-Fridman C (2004) FcgammaRIIB expression in diffuse large B-cell lymphomas does not alter the response to CHOP+rituximab (R-CHOP). Leukemia 18:2038–2040PubMedCrossRefGoogle Scholar
  66. 66.
    Rankin CT, Veri MC, Gorlatov S, Tuaillon N, Burke S, Huang L, Inzunza HD, Li H, Thomas S, Johnson S, Stavenhagen J, Koenig S, Bonvini E (2006) CD32B, the human inhibitory Fc-gamma receptor IIB, as a target for monoclonal antibody therapy of B-cell lymphoma. Blood 108:2384–2391PubMedCrossRefGoogle Scholar
  67. 67.
    Tartour E, de La Salle H, de La Salle C, Teillaud C, Camoin L, Galinha A, Latour S, Hanau D, Fridman WH, Sautes C (1993) Identification, in mouse macrophages and serum, of a soluble receptor for the Fc portion of IgG (Fc>=R) encoded by an alternatively spliced transcript of the Fc>=RII gene. Intern Immunol 5:859–868Google Scholar
  68. 68.
    Fridman WH, Teillaud JL, Bouchard C, Teillaud C, Astier A, Tartour E, Galon J, Mathiot C, Sautes C (1993) Soluble Fc gamma receptors. J Leukoc Biol 54:504–512PubMedGoogle Scholar
  69. 69.
    Astier A, de la Salle H, de la Salle C, Bieber T, Esposito-Farese ME, Freund M, Cazenave JP, Fridman WH, Teillaud JL, Hanau D (1994) Human epidermal Langerhans cells secrete a soluble receptor for IgG (Fc gamma RII/CD32) that inhibits the binding of immune complexes to Fc gamma R+ cells. J Immunol 152:201–212PubMedGoogle Scholar
  70. 70.
    Astier A, Merle-Beral H, de la Salle H, Moncuit J, Cazenave JP, Fridman WH, Hanau D, Teillaud JL (1997) Soluble Fcgamma receptor, Fc gammaRIIa2, is present in two forms in human serum and is increased in patients: with stage C chronic lymphocytic leukemia. Leuk Lymphoma 26:317–326PubMedGoogle Scholar
  71. 71.
    Galon J, Moldovan I, Galinha A, Provost-Marloie MA, Kaudewitz H, Roman-Roman S, Fridman WH, Sautes C (1998) Identification of the cleavage site involved in production of plasma soluble Fc gamma receptor type III (CD16). Eur J Immunol 28:2101–2107PubMedCrossRefGoogle Scholar
  72. 72.
    Wines BD, Gavin A, Powell MS, Steinitz M, Buchanan RR, Mark Hogarth P (2003) Soluble FcgammaRIIa inhibits rheumatoid factor binding to immune complexes. Immunology 109:246–254PubMedCrossRefGoogle Scholar
  73. 73.
    Enyedy EJ, Mitchell JP, Nambiar MP, Tsokos GC (2001) Defective FcgammaRIIb1 signaling contributes to enhanced calcium response in B cells from patients with systemic lupus erythematosus. Clin Immunol 101:130–135PubMedCrossRefGoogle Scholar
  74. 74.
    Oka T, Ouchida M, Koyama M, Ogama Y, Takada S, Nakatani Y, Tanaka T, Yoshino T, Hayashi K, Ohara N, Kondo E, Takahashi K, Tsuchiyama J, Tanimoto M, Shimizu K, Akagi T (2002) Gene silencing of the tyrosine phosphatase SHP1 gene by aberrant methylation in leukemias/lymphomas. Cancer Res 62:6390–6394PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Lydie Cassard
    • 1
    • 3
  • Joël Cohen-Solal
    • 1
    • 4
  • Sophie Camilleri-Broët
    • 1
    • 2
  • Emilie Fournier
    • 1
  • Wolf Herman Fridman
    • 1
  • Catherine Sautès-Fridman
    • 1
  1. 1.INSERM UMRs255, Université Paris 5 René DescartesUniversité Paris 6 Pierre et Marie Curie, Centre de Recherches des CordeliersParis Cedex 06France
  2. 2.Service d’anatomie pathologique, Hôtel Dieu, AP-HPUniversité Paris 6 Pierre et Marie CurieParis Cedex 04France
  3. 3.National Cancer InstituteBethesdaUSA
  4. 4.Department of MedicineColumbia UniversityNew YorkUSA

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