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Cancer Immunology, Immunotherapy

, Volume 57, Issue 7, pp 987–996 | Cite as

Immune modulation by melanoma and ovarian tumor cells through expression of the immunosuppressive molecule CD200

  • A. Siva
  • H. Xin
  • F. Qin
  • D. Oltean
  • K. S. Bowdish
  • A. Kretz-Rommel
Original Article

Abstract

Background and Objective

Immune escape by tumors can occur by multiple mechanisms, each a significant barrier to immunotherapy. We previously demonstrated that upregulation of the immunosuppressive molecule CD200 on chronic lymphocytic leukemia cells inhibits Th1 cytokine production required for an effective cytotoxic T cell response. CD200 expression on human tumor cells in animal models prevents human lymphocytes from rejecting the tumor; treatment with an antagonistic anti-CD200 antibody restored lymphocyte-mediated tumor growth inhibition. The current study evaluated CD200 expression on solid cancers, and its effect on immune response in vitro.

Methods and Results

CD200 protein was expressed on the surface of 5/8 ovarian cancer, 2/4 melanoma, 2/2 neuroblastoma and 2/3 renal carcinoma cell lines tested, but CD200 was absent on prostate, lung, breast, astrocytoma, or glioblastoma cell lines. Evaluation of patient samples by immunohistochemistry showed strong, membrane-associated CD200 staining on malignant cells of melanoma (4/4), ovarian cancer (3/3) and clear cell renal cell carcinoma (ccRCC) (2/3), but also on normal ovary and kidney. CD200 expression on melanoma metastases was determined by RT-QPCR, and was found to be significantly higher in jejunum metastases (2/2) and lung metastases (2/6) than in normal samples. Addition of CD200-expressing, but not CD200-negative solid tumor cell lines to mixed lymphocyte reactions downregulated the production of Th1 cytokines. Inclusion of antagonistic anti-CD200 antibody restored Th1 cytokine responses.

Conclusion

These data suggest that melanoma, ccRCC and ovarian tumor cells can express CD200, thereby potentially suppressing anti-tumor immune responses. CD200 blockade with an antagonistic antibody may permit an effective anti-tumor immune response in these solid tumor types.

Keywords

CD200 Immune evasion Therapeutic monoclonal antibodies 

References

  1. 1.
    Platsoucas CD, Fincke JE, Pappas J, Jung WJ, Heckel M, Schwarting R et al (2003) Immune responses to human tumors: development of tumor vaccines. Anticancer Res 23(3A):1969–1996PubMedGoogle Scholar
  2. 2.
    McWhirter JR, Kretz-Rommel A, Saven A, Maruyama T, Potter KN, Mockridge CI et al (2006) Antibodies selected from combinatorial libraries block a tumor antigen that plays a key role in immunomodulation. Proc Natl Acad Sci USA 103(4):1041–1046PubMedCrossRefGoogle Scholar
  3. 3.
    Kretz-Rommel A, Qin F, Dakappagari N, Ravey EP, McWhirter J, Oltean D et al (2007) CD200 expression on tumor cells suppresses antitumor immunity: new approaches to cancer immunotherapy. J Immunol 178(9):5595–5605PubMedGoogle Scholar
  4. 4.
    Moreaux J, Hose D, Reme T, Jourdan E, Hundemer M, Legouffe E et al (2006) CD200 is a new prognostic factor in multiple myeloma. Blood 108(13):4194–4197PubMedCrossRefGoogle Scholar
  5. 5.
    Tonks A, Hills R, White P, Rosie B, Mills KI, Burnett AK et al (2007) CD200 as a prognostic factor in acute myeloid leukaemia. Leukemia 21(3):566–568PubMedCrossRefGoogle Scholar
  6. 6.
    Barclay AN, Clark MJ, McCaughan GW (1986) Neuronal/lymphoid membrane glycoprotein MRC OX-2 is a member of the immunoglobulin superfamily with a light-chain-like structure. Biochem Soc Symp 51:149–157PubMedGoogle Scholar
  7. 7.
    Wright GJ, Jones M, Puklavec MJ, Brown MH, Barclay AN (2001) The unusual distribution of the neuronal/lymphoid cell surface CD200 (OX2) glycoprotein is conserved in humans. Immunology 102(2):173–179PubMedCrossRefGoogle Scholar
  8. 8.
    Barclay AN, Wright GJ, Brooke G, Brown MH (2002) CD200 and membrane protein interactions in the control of myeloid cells. Trends Immunol 23(6):285–290PubMedCrossRefGoogle Scholar
  9. 9.
    Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM et al (2000) Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 290(5497):1768–1771PubMedCrossRefGoogle Scholar
  10. 10.
    Gorczynski RM, Cattral MS, Chen Z, Hu J, Lei J, Min WP et al (1999) An immunoadhesin incorporating the molecule OX-2 is a potent immunosuppressant that prolongs allo- and xenograft survival. J Immunol 163(3):1654–1660PubMedGoogle Scholar
  11. 11.
    Clark DA, Yu G, Levy GA, Gorczynski RM (2001) Procoagulants in fetus rejection: the role of the OX-2 (CD200) tolerance signal. Semin Immunol 13(4):255–263PubMedCrossRefGoogle Scholar
  12. 12.
    Gorczynski RM, Chen Z, Clark DA, Kai Y, Lee L, Nachman J et al (2004) Structural and functional heterogeneity in the CD200R family of immunoregulatory molecules and their expression at the feto-maternal interface. Am J Reprod Immunol 52(2):147–163PubMedCrossRefGoogle Scholar
  13. 13.
    Freedman LR, Cerottini JC, Brunner KT (1972) In vivo studies of the role of cytotoxic T cells in tumor allograft immunity. J Immunol 109(6):1371–1378PubMedGoogle Scholar
  14. 14.
    Bevan MJ, Cohn M (1975) Cytotoxic effects of antigen- and mitogen-induced T cells on various targets. J Immunol 114(2 Pt 1):559–565PubMedGoogle Scholar
  15. 15.
    Chattopadhyay S, Chakraborty NG (2005) Continuous presence of Th1 conditions is necessary for longer lasting tumor-specific CTL activity in stimulation cultures with PBL. Hum Immunol 66(8):884–891PubMedCrossRefGoogle Scholar
  16. 16.
    Tendler CL, Burton JD, Jaffe J, Danielpour D, Charley M, McCoy JP et al (1994) Abnormal cytokine expression in Sezary and adult T-cell leukemia cells correlates with the functional diversity between these T-cell malignancies. Cancer Res 54(16):4430–4435PubMedGoogle Scholar
  17. 17.
    Takeuchi T, Ueki T, Sasaki Y, Kajiwara T, Li B, Moriyama N et al (1997) Th2-like response and antitumor effect of anti-interleukin-4 mAb in mice bearing renal cell carcinoma. Cancer Immunol Immunother 43(6):375–381PubMedCrossRefGoogle Scholar
  18. 18.
    Filella X, Alcover J, Zarco MA, Beardo P, Molina R, Ballesta AM (2000) Analysis of type T1 and T2 cytokines in patients with prostate cancer. Prostate 44(4):271–274PubMedCrossRefGoogle Scholar
  19. 19.
    Lauerova L, Dusek L, Simickova M, Kocak I, Vagundova M, Zaloudik J et al (2002) Malignant melanoma associates with Th1/Th2 imbalance that coincides with disease progression and immunotherapy response. Neoplasma 49(3):159–166PubMedGoogle Scholar
  20. 20.
    Tabata T, Hazama S, Yoshino S, Oka M (1999) Th2 subset dominance among peripheral blood T lymphocytes in patients with digestive cancers. Am J Surg 177(3):203–208PubMedCrossRefGoogle Scholar
  21. 21.
    Gorczynski RM, Chen Z, Kai Y, Wong S, Lee L (2004) Induction of tolerance-inducing antigen-presenting cells in bone marrow cultures in vitro using monoclonal antibodies to CD200R. Transplantation 77(8):1138–1144PubMedCrossRefGoogle Scholar
  22. 22.
    Fallarino F, Asselin-Paturel C, Vacca C, Bianchi R, Gizzi S, Fioretti MC et al (2004) Murine plasmacytoid dendritic cells initiate the immunosuppressive pathway of tryptophan catabolism in response to CD200 receptor engagement. J Immunol 173(6):3748–3754PubMedGoogle Scholar
  23. 23.
    Gorczynski RM, Lee L, Boudakov I (2005) Augmented induction of CD4 + CD25 +  Treg using monoclonal antibodies to CD200R. Transplantation 79(4):488–491PubMedGoogle Scholar
  24. 24.
    Mueller JP, Giannoni MA, Hartman SL, Elliott EA, Squinto SP, Matis LA et al (1997) Humanized porcine VCAM-specific monoclonal antibodies with chimeric IgG2/G4 constant regions block human leukocyte binding to porcine endothelial cells. Mol Immunol 34(6):441–452PubMedCrossRefGoogle Scholar
  25. 25.
    Ioannides CG, Fisk B, Fan D, Biddison WE, Wharton JT, O’Brian CA (1993) Cytotoxic T cells isolated from ovarian malignant ascites recognize a peptide derived from the HER-2/neu proto-oncogene. Cell Immunol 151(1):225–234PubMedCrossRefGoogle Scholar
  26. 26.
    Coleman S, Clayton A, Mason MD, Jasani B, Adams M, Tabi Z (2005) Recovery of CD8 + T-cell function during systemic chemotherapy in advanced ovarian cancer. Cancer Res 65(15):7000–7006PubMedCrossRefGoogle Scholar
  27. 27.
    Bondurant KL, Crew MD, Santin AD, O’Brien TJ, Cannon MJ (2005) Definition of an immunogenic region within the ovarian tumor antigen stratum corneum chymotryptic enzyme. Clin Cancer Res 11(9):3446–3454PubMedCrossRefGoogle Scholar
  28. 28.
    Romero P, Cerottini JC, Speiser DE (2006) The human T cell response to melanoma antigens. Adv Immunol 92:187–224PubMedGoogle Scholar
  29. 29.
    Faries MB, Morton DL (2005) Therapeutic vaccines for melanoma: current status. BioDrugs 19(4):247–260PubMedCrossRefGoogle Scholar
  30. 30.
    Gajewski TF, Meng Y, Harlin H (2006) Immune suppression in the tumor microenvironment. J Immunother (1997) 29(3):233–240CrossRefGoogle Scholar
  31. 31.
    Choi IH, Zhu G, Sica GL, Strome SE, Cheville JC, Lau JS et al (2003) Genomic organization and expression analysis of B7-H4, an immune inhibitory molecule of the B7 family. J Immunol 171(9):4650–4654PubMedGoogle Scholar
  32. 32.
    Kryczek I, Zou L, Rodriguez P, Zhu G, Wei S, Mottram P et al (2006) B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma. J Exp Med 203(4):871–881PubMedCrossRefGoogle Scholar
  33. 33.
    Simon I, Zhuo S, Corral L, Diamandis EP, Sarno MJ, Wolfert RL et al (2006) B7-h4 is a novel membrane-bound protein and a candidate serum and tissue biomarker for ovarian cancer. Cancer Res 66(3):1570–1575PubMedCrossRefGoogle Scholar
  34. 34.
    Tringler B, Liu W, Corral L, Torkko KC, Enomoto T, Davidson S et al (2006) B7-H4 overexpression in ovarian tumors. Gynecol Oncol 100(1):44–52PubMedCrossRefGoogle Scholar
  35. 35.
    Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB et al (2002) Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med 8(8):793–800PubMedGoogle Scholar
  36. 36.
    Blank C, Kuball J, Voelkl S, Wiendl H, Becker B, Walter B et al (2006) Blockade of PD-L1 (B7-H1) augments human tumor-specific T cell responses in vitro. Int J Cancer 119(2):317–327PubMedCrossRefGoogle Scholar
  37. 37.
    Ichikawa M, Chen L (2005) Role of B7-H1 and B7-H4 molecules in down-regulating effector phase of T-cell immunity: novel cancer escaping mechanisms. Front Biosci 10:2856–2860PubMedCrossRefGoogle Scholar
  38. 38.
    Curiel TJ, Wei S, Dong H, Alvarez X, Cheng P, Mottram P et al (2003) Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 9(5):562–567PubMedCrossRefGoogle Scholar
  39. 39.
    Kacinski BM, Stanley ER, Carter D, Chambers JT, Chambers SK, Kohorn EI et al (1989) Circulating levels of CSF-1 (M-CSF) a lymphohematopoietic cytokine may be a useful marker of disease status in patients with malignant ovarian neoplasms. Int J Radiat Oncol Biol Phys 17(1):159–164PubMedGoogle Scholar
  40. 40.
    Ramakrishnan S, Xu FJ, Brandt SJ, Niedel JE, Bast RC Jr, Brown EL (1989) Constitutive production of macrophage colony-stimulating factor by human ovarian and breast cancer cell lines. J Clin Invest 83(3):921–926PubMedCrossRefGoogle Scholar
  41. 41.
    Wu S, Boyer CM, Whitaker RS, Berchuck A, Wiener JR, Weinberg JB et al (1993) Tumor necrosis factor alpha as an autocrine and paracrine growth factor for ovarian cancer: monokine induction of tumor cell proliferation and tumor necrosis factor alpha expression. Cancer Res 53(8):1939–1944PubMedGoogle Scholar
  42. 42.
    Coukos G, Benencia F, Buckanovich RJ, Conejo-Garcia JR (2005) The role of dendritic cell precursors in tumour vasculogenesis. Br J Cancer 92(7):1182–1187PubMedCrossRefGoogle Scholar
  43. 43.
    Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL et al (2005) Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol 12(12):1005–1016PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • A. Siva
    • 1
  • H. Xin
    • 1
  • F. Qin
    • 1
  • D. Oltean
    • 1
  • K. S. Bowdish
    • 1
  • A. Kretz-Rommel
    • 1
  1. 1.Alexion Antibody Technologies, Inc.San DiegoUSA

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