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Lymphoma

Complementary IL-23 and IL-27 anti-tumor activities cause strong inhibition of human follicular and diffuse large B-cell lymphoma growth in vivo

Leukemia volume 26, pages 1365–1374 (2012)Cite this article

Abstract

Interleukin (IL)-23 and IL-27 are pro-inflammatory cytokines that share functional and structural similarities and may exert anti-tumor activities against solid and hematological malignancies. Here, we asked whether IL-23 and IL-27, alone or in combination, may act directly against human follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) cells. In this study, we demonstrated for the first time that human primary FL and DLBCL cells expressed complete and functional IL-23 and IL-27 receptors (R) and that IL-23 and IL-27 exerted anti-tumor activities in vitro and in vivo through different and complementary mechanisms. In vivo studies using severe combined immunodeficiency /non-obese diabetic mice-injected subcutaneously with human SU-DHL-4 cell line revealed that IL-23 inhibited directly tumor-cell proliferation, whereas IL-27 impaired the angiogenic program of lymphoma cells resulting in strong reduction of cell growth. In addition, combined treatment of IL-23 and IL-27 amplified the anti-tumor effects in vivo as compared with administration of each cytokine alone. These anti-tumor mechanisms were confirmed by in vitro experiments performed with primary lymphoma cells and cell lines. Our results strongly encourage the development of future clinical trials to evaluate the toxicity and efficacy of the IL-23 and IL-27 in lymphoma patients.

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References

  1. Nogai H, Dorken B, Lenz G . Pathogenesis of Non-Hodgkin's Lymphoma. J Clin Oncol 2011; 29: 1803–1811.

    Article  CAS  PubMed  Google Scholar 

  2. Montoto S, Davies AJ, Matthews J, Calaminici M, Norton AJ, Amess J et al. Risk and clinical implications of transformation of follicular lymphoma to diffuse large B-cell lymphoma. J Clin Oncol 2007; 25: 2426–2433.

    Article  PubMed  Google Scholar 

  3. Relander T, Johnson NA, Farinha P, Connors JM, Sehn LH, Gascoyne RD . Prognostic factors in follicular lymphoma. J Clin Oncol 2010; 28: 2902–2913.

    Article  CAS  PubMed  Google Scholar 

  4. Siddhartha G, Vijay P . R-CHOP versus R-CVP in the treatment of follicular lymphoma: a meta-analysis and critical appraisal of current literature. J Hematol Oncol 2009; 2: 14.

    Article  PubMed  PubMed Central  Google Scholar 

  5. McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol 1998; 16: 2825–2833.

    Article  CAS  PubMed  Google Scholar 

  6. Salles G, Seymour JF, Offner F, Lopez-Guillermo A, Belada D, Xerri L et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011; 377: 42–51.

    Article  CAS  PubMed  Google Scholar 

  7. Marcus R, Imrie K, Belch A, Cunningham D, Flores E, Catalano J et al. CVP chemotherapy plus rituximab compared with CVP as first-line treatment for advanced follicular lymphoma. Blood 2005; 105: 1417–1423.

    Article  CAS  PubMed  Google Scholar 

  8. Herold M, Haas A, Srock S, Neser S, Al-Ali KH, Neubauer A et al. Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: an East German Study Group Hematology and Oncology Study. J Clin Oncol 2007; 25: 1986–1992.

    Article  CAS  PubMed  Google Scholar 

  9. Younes A, Pro B, Robertson MJ, Flinn IW, Romaguera JE, Hagemeister F et al. Phase II clinical trial of interleukin-12 in patients with relapsed and refractory non-Hodgkin's lymphoma and Hodgkin's disease. Clin Cancer Res 2004; 10: 5432–5438.

    Article  CAS  PubMed  Google Scholar 

  10. Khan KD, Emmanouilides C, Benson Jr DM, Hurst D, Garcia P, Michelson G et al. A phase 2 study of rituximab in combination with recombinant interleukin-2 for rituximab-refractory indolent non-Hodgkin's lymphoma. Clin Cancer Res 2006; 12: 7046–7053.

    Article  CAS  PubMed  Google Scholar 

  11. Younes A, Sarris A, Consoli U, Rodriguez A, McLaughlin P, Huh Y et al. A pilot study of high-dose interleukin-3 treatment of relapsed follicular small cleaved-cell lymphoma: hematologic, immunologic, and clinical results. Blood 1996; 87: 1698–1703.

    CAS  PubMed  Google Scholar 

  12. Akamatsu N, Yamada Y, Hasegawa H, Makabe K, Asano R, Kumagai I et al. High IL-21 receptor expression and apoptosis induction by IL-21 in follicular lymphoma. Cancer Lett 2007; 256: 196–206.

    Article  CAS  PubMed  Google Scholar 

  13. de Totero D, Capaia M, Fabbi M, Croce M, Meazza R, Cutrona G et al. Heterogeneous expression and function of IL-21R and susceptibility to IL-21-mediated apoptosis in follicular lymphoma cells. Exp Hematol 2010; 38: 373–383.

    Article  CAS  PubMed  Google Scholar 

  14. Sarosiek KA, Malumbres R, Nechushtan H, Gentles AJ, Avisar E, Lossos IS . Novel IL-21 signaling pathway up-regulates c-Myc and induces apoptosis of diffuse large B-cell lymphomas. Blood 2010; 115: 570–580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Trinchieri G, Pflanz S, Kastelein RA . The IL-12 family of heterodimeric cytokines: new players in the regulation of T cell responses. Immunity 2003; 19: 641–644.

    Article  CAS  PubMed  Google Scholar 

  16. Shan BE, Hao JS, Li QX, Tagawa M . Antitumor activity and immune enhancement of murine interleukin-23 expressed in murine colon carcinoma cells. Cell Mol Immunol 2006; 3: 47–52.

    CAS  PubMed  Google Scholar 

  17. Yoshimoto T, Morishima N, Mizoguchi I, Shimizu M, Nagai H, Oniki S et al. Antiproliferative activity of IL-27 on melanoma. J Immunol 2008; 180: 6527–6535.

    Article  CAS  PubMed  Google Scholar 

  18. Hu J, Yuan X, Belladonna ML, Ong JM, Wachsmann-Hogiu S, Farkas DL et al. Induction of potent antitumor immunity by intratumoral injection of interleukin 23-transduced dendritic cells. Cancer Res 2006; 66: 8887–8896.

    Article  CAS  PubMed  Google Scholar 

  19. Oniki S, Nagai H, Horikawa T, Furukawa J, Belladonna ML, Yoshimoto T et al. Interleukin-23 and interleukin-27 exert quite different antitumor and vaccine effects on poorly immunogenic melanoma. Cancer Res 2006; 66: 6395–6404.

    Article  CAS  PubMed  Google Scholar 

  20. Shimizu M, Shimamura M, Owaki T, Asakawa M, Fujita K, Kudo M et al. Antiangiogenic and antitumor activities of IL-27. J Immunol 2006; 176: 7317–7324.

    Article  CAS  PubMed  Google Scholar 

  21. Cocco C, Canale S, Frasson C, Di Carlo E, Ognio E, Ribatti D et al. Interleukin-23 acts as antitumor agent on childhood B-acute lymphoblastic leukemia cells. Blood 2010; 116: 3887–3898.

    Article  CAS  PubMed  Google Scholar 

  22. Cocco C, Giuliani N, Di Carlo E, Ognio E, Storti P, Abeltino M et al. Interleukin-27 acts as multifunctional antitumor agent in multiple myeloma. Clin Cancer Res 2010; 16: 4188–4197.

    Article  CAS  PubMed  Google Scholar 

  23. Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000; 13: 715–725.

    Article  CAS  PubMed  Google Scholar 

  24. Pflanz S, Timans JC, Cheung J, Rosales R, Kanzler H, Gilbert J et al. IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells. Immunity 2002; 16: 779–790.

    Article  CAS  PubMed  Google Scholar 

  25. Parham C, Chirica M, Timans J, Vaisberg E, Travis M, Cheung J et al. A receptor for the heterodimeric cytokine IL-23 is composed of IL-12Rbeta1 and a novel cytokine receptor subunit, IL-23R. J Immunol 2002; 168: 5699–5708.

    Article  CAS  PubMed  Google Scholar 

  26. Pflanz S, Hibbert L, Mattson J, Rosales R, Vaisberg E, Bazan JF et al. WSX-1 and glycoprotein 130 constitute a signal-transducing receptor for IL-27. J Immunol 2004; 172: 2225–2231.

    Article  CAS  PubMed  Google Scholar 

  27. Hisada M, Kamiya S, Fujita K, Belladonna ML, Aoki T, Koyanagi Y et al. Potent antitumor activity of interleukin-27. Cancer Res 2004; 64: 1152–1156.

    Article  CAS  PubMed  Google Scholar 

  28. Airoldi I, Cocco C, Giuliani N, Ferrarini M, Colla S, Ognio E et al. Constitutive expression of IL-12R beta 2 on human multiple myeloma cells delineates a novel therapeutic target. Blood 2008; 112: 750–759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Airoldi I, Di Carlo E, Cocco C, Taverniti G, D’Antuono T, Ognio E et al. Endogenous IL-12 triggers an antiangiogenic program in melanoma cells. Proc Natl Acad Sci USA 2007; 104: 3996–4001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K et al. IL-23 promotes tumour incidence and growth. Nature 2006; 442: 461–465.

    Article  CAS  PubMed  Google Scholar 

  31. Lo CH, Lee SC, Wu PY, Pan WY, Su J, Cheng CW et al. Antitumor and antimetastatic activity of IL-23. J Immunol 2003; 171: 600–607.

    Article  CAS  PubMed  Google Scholar 

  32. Canale S, Cocco C, Frasson C, Seganfreddo E, Di Carlo E, Ognio E et al. Interleukin-27 inhibits pediatric B-acute lymphoblastic leukemia cell spreading in a pre-clinical model. Leukemia 2011; e-pub ahead of print 24 June 2011; doi:2010.1038/leu.2011.158.

    Article  CAS  PubMed  Google Scholar 

  33. Swerdlow S, Campo E, Harris N, Jaffe E, Pileri S, Stein H et al. WHO Classification of Tumors. IARC: Lyon, 2008.

    Google Scholar 

  34. Cocco C, Morandi F, Airoldi I . Interleukin-27 and interleukin-23 modulate human plasmacell functions. J Leukoc Biol 2011; 89: 729–734.

    Article  CAS  PubMed  Google Scholar 

  35. Ribatti D, Gualandris A, Bastaki M, Vacca A, Iurlaro M, Roncali L et al. New model for the study of angiogenesis and antiangiogenesis in the chick embryo chorioallantoic membrane: the gelatin sponge/chorioallantoic membrane assay. J Vasc Res 1997; 34: 455–463.

    Article  CAS  PubMed  Google Scholar 

  36. Airoldi I, Di Carlo E, Banelli B, Moserle L, Cocco C, Pezzolo A et al. The IL-12Rbeta2 gene functions as a tumor suppressor in human B cell malignancies. J Clin Invest 2004; 113: 1651–1659.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Livak KJ, Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402–408.

    Article  CAS  PubMed  Google Scholar 

  38. Larousserie F, Charlot P, Bardel E, Froger J, Kastelein RA, Devergne O . Differential effects of IL-27 on human B cell subsets. J Immunol 2006; 176: 5890–5897.

    Article  CAS  PubMed  Google Scholar 

  39. Johnson PW, Watt SM, Betts DR, Davies D, Jordan S, Norton AJ et al. Isolated follicular lymphoma cells are resistant to apoptosis and can be grown in vitro in the CD40/stromal cell system. Blood 1993; 82: 1848–1857.

    CAS  PubMed  Google Scholar 

  40. Paydas S . Anti-angiogenic strategies will be a revolution in lymphoma? Leuk Res 2010; 34: 552.

    Article  PubMed  Google Scholar 

  41. Koster A, van Krieken JH, Mackenzie MA, Schraders M, Borm GF, van der Laak JA et al. Increased vascularization predicts favorable outcome in follicular lymphoma. Clin Cancer Res 2005; 11: 154–161.

    CAS  PubMed  Google Scholar 

  42. Farinha P, Kyle AH, Minchinton AI, Connors JM, Karsan A, Gascoyne RD . Vascularization predicts overall survival and risk of transformation in follicular lymphoma. Haematologica 2010; 95: 2157–2160.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Jorgensen JM, Sorensen FB, Bendix K, Nielsen JL, Olsen ML, Funder AM et al. Angiogenesis in non-Hodgkin's lymphoma: clinico-pathological correlations and prognostic significance in specific subtypes. Leuk Lymphoma 2007; 48: 584–595.

    Article  CAS  PubMed  Google Scholar 

  44. Ganjoo KN, Moore AM, Orazi A, Sen JA, Johnson CS, An CS . The importance of angiogenesis markers in the outcome of patients with diffuse large B cell lymphoma: a retrospective study of 97 patients. J Cancer Res Clin Oncol 2008; 134: 381–387.

    Article  CAS  PubMed  Google Scholar 

  45. Jorgensen JM, Sorensen FB, Bendix K, Nielsen JL, Funder A, Karkkainen MJ et al. Expression level, tissue distribution pattern, and prognostic impact of vascular endothelial growth factors VEGF and VEGF-C and their receptors Flt-1, KDR, and Flt-4 in different subtypes of non-Hodgkin lymphomas. Leuk Lymphoma 2009; 50: 1647–1660.

    Article  PubMed  Google Scholar 

  46. Labidi SI, Menetrier-Caux C, Chabaud S, Chassagne C, Sebban C, Gargi T et al. Serum cytokines in follicular lymphoma. Correlation of TGF-beta and VEGF with survival. Ann Hematol 2010; 89: 25–33.

    Article  CAS  PubMed  Google Scholar 

  47. Seymour JF, Talpaz M, Cabanillas F, Wetzler M, Kurzrock R . Serum interleukin-6 levels correlate with prognosis in diffuse large-cell lymphoma. J Clin Oncol 1995; 13: 575–582.

    Article  CAS  PubMed  Google Scholar 

  48. Pazgal I, Boycov O, Shpilberg O, Okon E, Bairey O . Expression of VEGF-C, VEGF-D and their receptor VEGFR-3 in diffuse large B-cell lymphomas. Leuk Lymphoma 2007; 48: 2213–2220.

    Article  CAS  PubMed  Google Scholar 

  49. Gratzinger D, Zhao S, Tibshirani RJ, Hsi ED, Hans CP, Pohlman B et al. Prognostic significance of VEGF, VEGF receptors, and microvessel density in diffuse large B cell lymphoma treated with anthracycline-based chemotherapy. Lab Invest 2008; 88: 38–47.

    Article  CAS  PubMed  Google Scholar 

  50. Emilie D, Coumbaras J, Raphael M, Devergne O, Delecluse HJ, Gisselbrecht C et al. Interleukin-6 production in high-grade B lymphomas: correlation with the presence of malignant immunoblasts in acquired immunodeficiency syndrome and in human immunodeficiency virus-seronegative patients. Blood 1992; 80: 498–504.

    CAS  PubMed  Google Scholar 

  51. Tageja N, Padheye S, Dandawate P, Al-Katib A, Mohammad RM . New targets for the treatment of follicular lymphoma. J Hematol Oncol 2009; 2: 50.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Arnold AA, Aboukameel A, Chen J, Yang D, Wang S, Al-Katib A et al. Preclinical studies of Apogossypolone: a new nonpeptidic pan small-molecule inhibitor of Bcl-2, Bcl-XL and Mcl-1 proteins in follicular small cleaved cell lymphoma model. Mol Cancer 2008; 7: 20.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Mohammad RM, Mohamed AN, Smith MR, Jawadi NS, al-Katib A . A unique EBV-negative low-grade lymphoma line (WSU-FSCCL) exhibiting both t(14;18) and t(8;11). Cancer Genet Cytogenet 1993; 70: 62–67.

    Article  CAS  PubMed  Google Scholar 

  54. Younes A, Vose JM, Zelenetz AD, Smith MR, Burris HA, Ansell SM et al. A Phase 1b/2 trial of mapatumumab in patients with relapsed/refractory non-Hodgkin's lymphoma. Br J Cancer 2010; 103: 1783–1787.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Sethi G, Ahn KS, Aggarwal BB . Targeting nuclear factor-kappa B activation pathway by thymoquinone: role in suppression of antiapoptotic gene products and enhancement of apoptosis. Mol Cancer Res 2008; 6: 1059–1070.

    Article  CAS  PubMed  Google Scholar 

  56. Zou W, Restifo NP . T(H)17 cells in tumour immunity and immunotherapy. Nat Rev Immunol 2010; 10: 248–256.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Alexandrakis MG, Pappa CA, Miyakis S, Sfiridaki A, Kafousi M, Alegakis A et al. Serum interleukin-17 and its relationship to angiogenic factors in multiple myeloma. Eur J Intern Med 2006; 17: 412–416.

    Article  CAS  PubMed  Google Scholar 

  58. Wilke CM, Kryczek I, Wei S, Zhao E, Wu K, Wang G et al. Th17 cells in cancer: help or hindrance? Carcinogenesis 2011; 32: 643–649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Kryczek I, Banerjee M, Cheng P, Vatan L, Szeliga W, Wei S et al. Phenotype, distribution, generation, and functional and clinical relevance of Th17 cells in the human tumor environments. Blood 2009; 114: 1141–1149.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Lee YK, Mukasa R, Hatton RD, Weaver CT . Developmental plasticity of Th17 and Treg cells. Curr Opin Immunol 2009; 21: 274–280.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by grants from Associazione Italiana Ricerca sul Cancro (AIRC) Milano, Italy (grant number 4014 to IA), Italian Ministry of Health (RF, RC, 5/1000, Progetto Strategico Oncologico 2006 rif070701), and Fondazione Cassa di Risparmio della Provincia di Chieti (CariChieti), Italy to EDC.

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  1. C Cocco and E Di Carlo: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental and Laboratory Medicine, A.I.R.C. Laboratory of Immunology and Tumors, G. Gaslini Institute, Genova, Italy

    C Cocco, S Canale, A Zorzoli & I Airoldi

  2. Department of Oncology and Experimental Medicine, ‘G d’Annunzio’ University and Ce S I Aging Research Center, ‘G d’Annunzio’ University Foundation, Chieti, Italy

    E Di Carlo

  3. Department of Pathology, Laboratory of Molecular Diagnosis, National Institute for Cancer Research, Genova, Italy

    S Zupo

  4. Department of Human Anatomy and Histology, University of Bari, Bari, Italy

    D Ribatti

  5. Department of Experimental and Laboratory Medicine, Laboratory of Oncology, G. Gaslini Institute, Genova, Italy

    F Morandi

  6. Animal Model Facility, National Institute for Cancer Research, Genova, Italy

    E Ognio

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Cocco, C., Di Carlo, E., Zupo, S. et al. Complementary IL-23 and IL-27 anti-tumor activities cause strong inhibition of human follicular and diffuse large B-cell lymphoma growth in vivo. Leukemia 26, 1365–1374 (2012). https://doi.org/10.1038/leu.2011.363

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