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Prospects for CD40-directed experimental therapy of human cancer

Cancer Gene Therapy volume 10, pages 1–13 (2003)Cite this article

Abstract

CD40, a member of the tumor necrosis factor receptor (TNF-R) family, is a surface receptor best known for its capacity to initiate multifaceted activation signals in normal B cells and dendritic cells (DCs). CD40-related treatment approaches have been considered for the experimental therapy of human leukemias, lymphomas, and multiple myeloma, based on findings that CD40 binding by its natural ligand (CD40L), CD154, led to growth modulation of malignant B cells. Recent studies also exploited the selective expression of the CD40 receptor on human epithelial and mesenchymal tumors but not on most normal, nonproliferating epithelial tissues. Ligation of CD40 on human breast, ovarian, cervical, bladder, non small cell lung, and squamous epithelial carcinoma cells was found to produce a direct growth-inhibitory effect through cell cycle blockage and/or apoptotic induction with no overt side effects on their normal counterparts. CD154 treatment also heightened tumor rejection immune responses through DC activation, and by increasing tumor immunogenicity through up-regulation of costimulatory molecule expression and cytokine production of epithelial cancer cells. These immunopotentiating features can produce a “bystander effect” through which the CD40-negative tumor subset is eliminated by activated tumor-reactive cytotoxic T cells. However, the potential risk of systemic inflammation and autoimmune consequences remains a concern for systemic CD154-based experimental therapy. The promise of CD154 as a tumor therapeutic agent to directly modulate tumor cell growth, and indirectly activate antitumor immune response, may depend on selective and/or restricted CD154 expression within the tumor microenvironment. This may be achieved by inoculating cancer vaccines of autologous cancer cells that have been transduced ex vivo with CD154, as documented by recently clinical trials. This review summarizes recent findings on CD154 recombinant protein- and gene therapy–based tumor treatment approaches, and examines our understanding of the multifaceted molecular mechanisms of CD154–CD40 interactions.

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References

  1. Paulie S, Rosén A & Ehlin-Henrikisson B, et al. The human B lymphocyte and carcinoma antigen, CDw40, is a phosphoprotein involved in growth signal transduction. J Immunol. 1989; 142: 590–595.

    CAS  PubMed  Google Scholar 

  2. Armitage RJ, Sato TA & Macduff BM, et al. Identification of a source of biologically active CD40 ligand. Eur J Immunol. 1992; 22: 2071–2076.

    Article  CAS  PubMed  Google Scholar 

  3. Van Kooten C & Banchereau J . CD40–CD40 ligand. J Leukoc Biol. 2000; 67: 2–17.

    Article  CAS  PubMed  Google Scholar 

  4. Biancone L, Cantaluppi V & Camussi G . CD40–CD154 interactions in experimental and human disease. Int J Mol Med. 1999; 3: 343–353.

    CAS  PubMed  Google Scholar 

  5. Ruggiero G, Caceres EM & Voordouw A, et al. CD40 expressed on thymic epithelial cells provides costimulation for proliferation but not for apoptosis of human thymocytes. J Immunol. 1996; 156: 3737–3746.

    CAS  PubMed  Google Scholar 

  6. Gauchat JF, Aubry JP & Mazzei G, et al. Human CD40 ligand: molecular cloning, cellular distribution and regulation of expression by factors controlling IgE production. FEBS Lett. 1993; 315: 259–266.

    Article  CAS  PubMed  Google Scholar 

  7. Uckun FM, Gajil-Peczalska K & Myers DE, et al. Temporal association of CD40 antigen expression with discrete stages of human B-cell ontogeny and the efficacy of anti-CD40 immunotoxins against clonogenic B-lineage acute lymphoblastic leukemia as well as B-lineage non-Hodgkin's lymphoma cells. Blood. 1990; 76: 2449–2456.

    Article  CAS  PubMed  Google Scholar 

  8. Rothstein TL, Wang JKM & Panka DJ, et al. Protection against Fas-dependent Th1-mediated apoptosis by antigen receptor engagement in B cells. Nature. 1995; 374: 163–165.

    Article  CAS  PubMed  Google Scholar 

  9. Garrone P, Neidhardt EM & Garcia E, et al. Fas ligation induces apoptosis of CD40-activated human B lymphocytes. J Exp Med. 1995; 182: 1265–1273.

    Article  CAS  PubMed  Google Scholar 

  10. Miyashita T, McIlrath MJ & Grammer AC, et al. Bidirectional regulation of human B cell responses by CD40–CD40 ligand interactions. J Immunol. 1997; 158: 4620–4633.

    CAS  PubMed  Google Scholar 

  11. Majlessi L & Bordenave G . Role of CD40 in a T cell–mediated negative regulation of Ig production. J Immunol. 2001; 166: 841–847.

    Article  CAS  PubMed  Google Scholar 

  12. Funakoshi S, Longo DL & Beckwith M, et al. Inhibition of human B-cell lymphoma growth by CD40 stimulation. Blood. 1994; 83: 2787–2794.

    Article  CAS  PubMed  Google Scholar 

  13. Arpin C, Dechanet J & Van Kooten C, et al. Generation of memory B cells and plasma cells in vitro. Science. 1995; 268: 720–722.

    Article  CAS  PubMed  Google Scholar 

  14. Quiding-Jarbrink M, Lakew M & Nordstrom I, et al. Human circulating specific antibody-forming cells after systemic and mucosal immunizations: differential homing commitments and cell surface differentiation markers. Eur J Immunol. 1995; 25: 322–327.

    Article  CAS  PubMed  Google Scholar 

  15. Aruffo A, Farrington M & Hollenbaugh D, et al. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell. 1993; 72: 291–300.

    Article  CAS  PubMed  Google Scholar 

  16. Costello RT, Gastaut JA & Olive D . What is the real role of CD40 in cancer immunotherapy?. Immunol Today. 1999; 20: 488–493.

    Article  CAS  PubMed  Google Scholar 

  17. Young LS, Eliopoulos AG & Gallagher NJ, et al. CD40 and epithelial cells: across the great divide. Immunol Today. 1998; 19: 502–506.

    Article  CAS  PubMed  Google Scholar 

  18. Grewal IS & Flavell RA . CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol. 1998; 16: 111–155.

    Article  CAS  PubMed  Google Scholar 

  19. Roy M, Aruffo A, Ledbetter J, Linsley P, Kehry M & Noelle R . Studies on the interdependence of gp39 and B7 expression and function during antigen-specific immune responses. Eur J Immunol. 1995; 25: 596–603.

    Article  CAS  PubMed  Google Scholar 

  20. Grewal IS, Xu J & Flavell RA . Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand. Nature. 1995; 378: 617–622.

    Article  CAS  PubMed  Google Scholar 

  21. Sin JI, Kim JJ & Zhang D, et al. Modulation of cellular responses by plasmid CD40L: CD40L plasmid vectors enhance antigen-specific helper T cell type 1 CD4+ T cell mediated protective immunity against herpes simplex virus type 2 in vivo. Hum Gene Ther. 2001; 12: 1091–1102.

    Article  CAS  PubMed  Google Scholar 

  22. Kiener PA, Moran-Dvais P & Rankin BM, et al. Stimulation of CD40 with purified soluble gp39 induces proinflammatory responses in human monocytes. J Immunol. 1995; 155: 4917–4925.

    CAS  PubMed  Google Scholar 

  23. Cella M, Scheidegger D & Palmer-Lehman K, et al. Ligation of CD40 on dendritic cells triggers production of high levels of interleukin-12 and enhances T cell stimulatory capacity: T–T help via APC activation. J Exp Med. 1996; 184: 747–752.

    Article  CAS  PubMed  Google Scholar 

  24. Bleharski JR, Niazi KR & Sieling PA, et al. Signaling lymphocytic activation molecule is expressed on CD40 ligand–activated dendritic cells and directly augments production of inflammatory cytokines. J Immunol. 2001; 167: 3174–3181.

    Article  CAS  PubMed  Google Scholar 

  25. Carbone E, Ruggiero G & Terrazzano G, et al. A new mechanism of NK cell cytotoxicity activation: the CD40–CD40 ligand interaction. J Exp Med. 1997; 185: 2053–2060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Singh SR, Casper K, Summers S & Swerlick RA . CD40 expression and function on human dermal microvascular endothelial cells: role in cutaneous inflammation. Clin Exp Dermatol. 2001; 26: 434–440.

    Article  CAS  PubMed  Google Scholar 

  27. Kitagawa M, Suzuki H & Adachi Y, et al. Interferon-gamma enhances interleukin 12 production in rheumatoid synovial cells via CD40–CD154 dependent and independent pathways. J Rheumatol. 2001; 28: 1764–1771.

    CAS  PubMed  Google Scholar 

  28. De Miguel S, Galocha B & Jover JA, et al. Mechanisms of CD23 hyperexpression on B cells from patients with rheumatoid arthritis. J Rheumatol. 2001; 28: 1222–1228.

    CAS  PubMed  Google Scholar 

  29. Lutgens E, Gorelik L & Daemen MJ, et al. Requirement for CD154 in the progression of atherosclerosis. Nat Med. 1999; 5: 1313–1316.

    Article  CAS  PubMed  Google Scholar 

  30. Schonbeck U & Libby P . The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci. 2001; 58: 4–43.

    Article  CAS  PubMed  Google Scholar 

  31. Kirk AD, Burkly LC & Batty DS, et al. Treatment with humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in nonhuman primates. Nat Med. 1999; 5: 686–693.

    Article  CAS  PubMed  Google Scholar 

  32. Taylor PA, Lees CJ & Waldmann H, et al. Requirements for the promotion of allogeneic engraftment by anti-CD154 (anti-CD40L) monoclonal antibody under nonmyeloablative conditions. Blood. 2001; 98: 467–474.

    Article  CAS  PubMed  Google Scholar 

  33. Jensen J, Krakauer M & Sellebjerg F . Increased T cell expression of CD154 (CD40-ligand) in multiple sclerosis. Eur J Neurol. 2001; 8: 321–328.

    Article  CAS  PubMed  Google Scholar 

  34. Brams P, Black A & Padlan EA, et al. A humanized anti-human CD154 monoclonal antibody blocks CD154–CD40 mediated human B cell activation. Int Immunopharmacol. 2001; 1: 277–294.

    Article  CAS  PubMed  Google Scholar 

  35. Im SH, Barchan D & Maiti PK, et al. Blockade of CD40 ligand suppresses chronic experimental myasthenia gravis by down-regulation of Th1 differentiation and up-regulation of CTLA-4. J Immunol. 2001; 166: 6893–6898.

    Article  CAS  PubMed  Google Scholar 

  36. Denfeld RW, Hollenbaugh D & Fehrenbach A, et al. CD40 is functionally expressed on human keratinocytes. Eur J Immunol. 1996; 26: 2329–2334.

    Article  CAS  PubMed  Google Scholar 

  37. Bata-Csorgo Z, Hammerberg C, Voorhees JJ & Cooper KD . Flow cytometric identification of proliferative subpopulations within normal human epidermis and the localization of the primary hyperproliferative population in psoriasis. J Exp Med. 1993; 178: 1271–1281.

    Article  CAS  PubMed  Google Scholar 

  38. Hess S & Engelmann H . A novel function of CD40: induction of cell death in transformed cells. J Exp Med. 1996; 183: 159–167.

    Article  CAS  PubMed  Google Scholar 

  39. Thomas WD, Smith MJ, Si Z & Hersey P . Expression of the co-stimulatory molecule CD40 on melanoma cells. Int J Cancer. 1996; 68: 795–801.

    Article  CAS  PubMed  Google Scholar 

  40. Johnson PWM, Watt SM & Betts DR, 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.

    Article  CAS  PubMed  Google Scholar 

  41. Umetsu DT, Esserman L & Donlon TA, et al. Induction of proliferation of human follicular (B type) lymphoma cells by cognate interaction with CD4+ T cell clones. J Immunol. 1990; 144: 2550–2557.

    CAS  PubMed  Google Scholar 

  42. Kluin-Nelemans HC, Beverstock GC & Mollevanger P, et al. Proliferation and cytogenetic analysis of hairy cell leukemia upon stimulation via the CD40 antigen. Blood. 1994; 84: 3134–3141.

    Article  CAS  PubMed  Google Scholar 

  43. Fluckiger AC, Durand I & Banchereau J . Interleukin 10 induces apoptotic cell death of B-chronic lymphocytic leukemia cells. J Exp Med. 1994; 179: 91–99.

    Article  CAS  PubMed  Google Scholar 

  44. Schattner EJ, Mascarenhas J & Bishop J, et al. CD4+ T-cell induction of Fas-mediated apoptosis in Burkitt's lymphoma B cells. Blood. 1996; 88: 1375–1382.

    Article  CAS  PubMed  Google Scholar 

  45. Berberich I, Shu G & Siebelt F, et al. Cross-linking CD40 on B cells preferentially induces stress-activated protein kinases rather than mitogen-activated protein kinases. EMBO J. 1996; 15: 92–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Aldinucci D, Poletto D & Nanni P, et al. Direct effects of CD40L on CD40+ AML blasts: proliferation, self renewal, rescue from apoptosis and production of cytokines (Abstract). Blood. 1991; 98: 589a

    Google Scholar 

  47. Marches R, Racila E & Tucker TF, et al. Tumour dormancy and cell signalling: III. Role of hypercrosslinking of IgM and CD40 on the induction of cell cycle arrest and apoptosis in B lymphoma cells. Ther Immunol. 1995; 2: 125–136.

    CAS  PubMed  Google Scholar 

  48. Vyth-Dreese FA, Boot H & Dellemijn TA, et al. Localization in situ of costimulatory molecules and cytokines in B-cell non-Hodgkin's lymphoma. Immunology. 1998; 94: 580–586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tong AW, Zhang BQ, Mues G, Hanson T, Solano M & Stone MJ . Anti-CD40 antibody binding modulates human multiple myeloma clonogenicity in vitro. Blood. 1994; 84: 3026–3033.

    Article  CAS  PubMed  Google Scholar 

  50. Pellat-Deceunynck C, Bataille R & Robilard N, et al. Expression of CD28 and CD40 in human myeloma cells: a comparative study with normal plasma cells. Blood. 1994; 84: 2597–2603.

    Article  CAS  PubMed  Google Scholar 

  51. Tong AW, Seamour B & Chen J, et al. CD40 ligand–induced apoptosis is Fas-independent in human multiple myeloma cells. Leuk Lymphoma. 2000; 36: 543–558.

    Article  CAS  PubMed  Google Scholar 

  52. Teoh G, Tai YT & Urashima M, et al. CD40 activation mediates p53-dependent cell cycle regulation in human multiple myeloma cell lines. Blood. 2000; 95: 1039–1046.

    Article  CAS  PubMed  Google Scholar 

  53. Bergamo A, Bataille R & Pellat-Deceunynck C, et al. CD40 and CD95 induce programmed cell death in the human myeloma cell line XG2. Br J Haematol. 1997; 97, (652-5-3132

    Article  CAS  PubMed  Google Scholar 

  54. Eliopoulos AG, Dawson CW & Mosialos G, et al. CD40-induced growth inhibition in epithelial cells is mimicked by Epstein-Barr virus–encoded LMP-1: involvement of TRAF3 as a common mediator. Oncogene. 1996; 13: 2243–2254.

    CAS  PubMed  Google Scholar 

  55. Eliopoulos AG, Stack M & Dawson CW, et al. Epstein-Barr virus–encoded LMP-1 and CD40 mediate IL-6 production in epithelial cells via an NF-kappaB pathway involving TNF receptor–associated factors. Oncogene. 1997; 14: 2889–2916.

    Article  Google Scholar 

  56. Loro LL, Ohlsson M & Vintermyr OK, et al. Maintained CD40 and loss of polarized CD40 ligand expression in oral squamous cell carcinoma. Anticancer Res. 2001; 21: 113–117.

    CAS  PubMed  Google Scholar 

  57. Kluth B, Hess S & Engelmann H, et al. Endothelial expression of CD40 in renal cell carcinoma. Cancer Res. 1997; 57: 891–899.

    CAS  PubMed  Google Scholar 

  58. Tong AW, Papayoti M & Netto G, et al. The growth inhibitory effects of CD40 ligand (CD154) and its endogenous expression in human breast cancer. Clin Cancer Res. 2001; 7: 691–703.

    CAS  PubMed  Google Scholar 

  59. Yamada M, Shiroko T & Kawaguchi Y, et al. CD40–CD40 ligand (CD154) engagement is required but not sufficient for modulating MHC class I, ICAM-1 and Fas expression and proliferation of human non-small cell lung tumors. Int J Cancer. 2001; 92: 589–599.

    Article  CAS  PubMed  Google Scholar 

  60. Von Leoprechting A, van der Bruggen P & Pahl HL, et al. Stimulation of CD40 on immunogenic human malignant melanomas augments their cytotoxic T lymphocyte–mediated lysis and induces apoptosis. Cancer Res. 1999; 59: 1287–1294.

    CAS  PubMed  Google Scholar 

  61. Funakoshi S, Taub DD & Anver MR, et al. Immunologic and hematopoietic defects of CD40 stimulation after syngeneic bone marrow transplantation in mice. J Clin Invest. 1997; 99: 449–484.

    Article  Google Scholar 

  62. Hirano A, Longo DL & Taub DD, et al. Inhibition of human breast carcinoma growth by a soluble recombinant human CD40 ligand. Blood. 1999; 93: 2999–3007.

    Article  CAS  PubMed  Google Scholar 

  63. Hollenbaugh D, Grosmaire LS & Kullas CD, et al. The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity. EMBO J. 1992; 11: 4313–4321.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Morris AE, Remmele RL & Klinke R, et al. Incorporation of an isoleucine zipper motif enhances the biological activity of soluble CD40L (CD154). J Biol Chem. 1999; 274: 418–423.

    Article  CAS  PubMed  Google Scholar 

  65. Pullen SS, Labadia ME & Ingraham RH, et al. High-affinity interactions of tumor necrosis factor receptor–associated factors (TRAFs) and CD40 require TRAF trimerization and CD40 multimerization. Biochemistry. 1999; 38: 10168–10177.

    Article  CAS  PubMed  Google Scholar 

  66. Camp BJ, Dyhrman ST & Memoli VA, et al. In situ cytokine production by breast cancer tumor–infiltrating lymphocytes. Ann Surg Oncol. 1996; 3: 176–184.

    Article  CAS  PubMed  Google Scholar 

  67. Basolo F, Calvo S & Fiore L, et al. Production of cytokines and response to them in normal and transformed human mammary epithelial cells. Ann NY Acad Sci. 1993; 698: 126–130.

    Article  CAS  PubMed  Google Scholar 

  68. Ghamande S, Hylander BL & Oflazoglu E, et al. Recombinant CD40 ligand therapy has significant anti-tumor effects on CD40-positive ovarian tumor xenografts grown in SCID mice and demonstrates an augmented effect with cisplatin. Cancer Res. 2001; 61: 7556–7562.

    CAS  PubMed  Google Scholar 

  69. Wingett DG, Vestal RE & Forcier K, et al. CD40 is functionally expressed on human breast carcinomas: variable inducibility by cytokines and enhancement of Fas-mediated apoptosis. Breast Cancer Res Treat. 1998; 50: 27–36.

    Article  CAS  PubMed  Google Scholar 

  70. Posner MR, Cavacini LA & Upton MP, et al. Surface membrane–expressed CD40 is present on tumor cells from squamous cell cancer of the head and neck in vitro and in vivo and regulates cell growth in tumor cell lines. Clin Cancer Res. 1999; 5: 2261–2270.

    CAS  PubMed  Google Scholar 

  71. Gruss H, Boiani N & Williams DE, et al. Pleiotropic effects of the CD30 ligand on CD30-expressing cells and lymphoma cell lines. Blood. 1994; 83: 2045–2056.

    Article  CAS  PubMed  Google Scholar 

  72. Clement MV & Stamenkovic I . Fas and tumor necrosis factor receptor–mediated cell death: similarities and distinctions. J Exp Med. 1994; 180: 557–567.

    Article  CAS  PubMed  Google Scholar 

  73. Clement MV & Stamenkovic I . Superoxide anion is a natural inhibitor of Fas-mediated cell death. EMBO J. 1996; 15: 216–225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Ghetie MA, Pickler LJ & Richardson JA, et al. Anti-CD19 inhibits the growth of human B-cell tumor lines in vitro and of Daudi cells in SCID mice by inducing cell cycle arrest. Blood. 1994; 83: 1329–1336.

    Article  CAS  PubMed  Google Scholar 

  75. Ziebold JL, Hixon J, Boyd A & Murphy WJ . Differential effects of CD40 stimulation on normal and neoplastic cell growth. Arch Immunol Ther Exp. 2000; 48: 225–233.

    CAS  Google Scholar 

  76. Ni CZ, Welsh K & Leo E, et al. Molecular basis for CD40 signaling mediated by TRAF3. Proc Natl Acad Sci USA. 2000; 97: 10395–10399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. McWhirter SM, Pullen SS & Werneburg BG, et al. Structural and biochemical analysis of signal transduction by the TRAF family of adapter proteins. Cold Spring Harbor Symp Quant Biol. 1999; LXIV: 551–562.

    Article  Google Scholar 

  78. Werneberg BG, Zoog SJ & Dang TTA, et al. Molecular characterization of CD40 signaling intermediates. J Biol Chem. 2001; 276: 43334–43342.

    Article  CAS  Google Scholar 

  79. Arch RH, Gedrich RW & Thompson CB . Tumor necrosis factor receptor–associated factors (TRAFs) — a family of adapter proteins that regulates life and death. Genes Dev. 1998; 12: 2821–2830.

    Article  CAS  PubMed  Google Scholar 

  80. Hu HM, O'Rourke K, Boguski MS & Dixit VM . A novel ring finger protein interacts with the cytoplasmic domain of CD40. J Biol Chem. 1994; 269: 30069–30072.

    Article  CAS  PubMed  Google Scholar 

  81. Pullen SS, Miller HG & Everdeen DS, et al. CD40–tumor necrosis factor receptor–associated factor (TRAF) interactions: regulation of CD40 signaling through multiple TRAF binding sites and TRAF hetero-oligomerization. Biochemistry. 1998; 7: 11836–11845.

    Article  Google Scholar 

  82. Galibert L, Tometsko ME & Anderson DM, et al. The involvement of multiple tumor necrosis factor receptor (TNFR)–associated factors in the signaling mechanisms of receptor activator of NFκB, a member of the TNFR superfamily. J Biol Chem. 1998; 273: 34120–34127.

    Article  CAS  PubMed  Google Scholar 

  83. Zapata JM, Krajewska M & Krajewski S, et al. TNFR-associated factor family protein expression in normal tissues and lymphoid malignancies. J Immunol. 2000; 165: 5084–5096.

    Article  CAS  PubMed  Google Scholar 

  84. Rothe M, Pan MG & Henzel WJ, et al. The TNFR2–TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins. Cell. 1996; 82: 1243–1252.

    Google Scholar 

  85. Ishida T, Tojo T & Aoki T, et al. TRAF5, a novel tumor necrosis factor receptor–associated factor family protein, mediates CD40 signaling. Proc Natl Acad Sci USA. 1996; 93: 9437–9442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hu BT & Insel RA . Up-regulation of telomerase in human B lymphocytes occurs independently of cellular proliferation and with expression of the telomerase catalytic subunit. Eur J Immunol. 1999; 29: 3745–3753.

    Article  CAS  PubMed  Google Scholar 

  87. Herold MJ, Kuss AW, Kraus C & Berberich I . Mitochondria-dependent caspase-9 activation is necessary for antigen receptor–mediated effector caspase activation and apoptosis in WEHI 231 lymphoma cells. J Immunol. 2002; 168: 3902–3909.

    Article  CAS  PubMed  Google Scholar 

  88. Wang C, Mayo M & Korneleck R, et al. NFκB antiapoptosis: induction of TRAF1 and TRAF2 and cIAP1 and cIAP2 to suppress caspase 8 activation. Science. 1996; 281: 1680–1683.

    Article  Google Scholar 

  89. Hostager BS & Bishop GA . Cutting edge: contrasting roles of TNF receptor–associated factor 2 (TRAF2) and TRAF3 in CD40-activated B lymphocyte. J Immunol. 1999; 162: 6307–6311.

    CAS  PubMed  Google Scholar 

  90. Grammer AC, Swantek JL & McFarland RD, et al. TNF receptor–associated factor-3 signaling mediates activation of p38 and Jun N-terminal kinase, cytokine secretion and Ig production following ligation of CD40 on human B cells. J Immunol. 1998; 161: 1183–1193.

    CAS  PubMed  Google Scholar 

  91. Pearson LL, Castle BE & Kehry MR . CD40-mediated signaling in monocytic cells: up-regulation of tumor necrosis factor receptor–associated factor mRNAs and activation of mitogen-activated protein kinase signaling pathways. Int Immunol. 2001; 13: 273–283.

    Article  CAS  PubMed  Google Scholar 

  92. Leo E, Welsh K & Matsuzawa S, et al. Differential requirements for TRAF-family proteins in CD40-mediated induction of NFκB and JNK activation. J Biol Chem. 1999; 274: 22414–22422.

    Article  CAS  PubMed  Google Scholar 

  93. Baker SJ & Reddy EP . Modulation of life and death by the TNF receptor family. Oncogene. 1998; 17: 3261–3270.

    Article  PubMed  Google Scholar 

  94. Grell M, Zimmermann G & Gottfried E, et al. Induction of cell death by tumour necrosis factor (TNF) receptor 2, CD40 and CD30: a role for TNF-R1 activation by membrane-anchored TNF. EMBO J. 1999; 18: 3034–3043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Gallagher NJ, Eliopoulous AG & Aganthangelo A, et al. CD40 activation in epithelial ovarian carcinoma cells modulates growth, apoptosis, and cytokine secretion. Mol Pathol. 2002; 55: 110–120.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Baker MP, Eliopoulos AG & Young LS, et al. Prolonged phenotypic, functional, and molecular change in group I Burkitt lymphoma cells on short-term exposure to CD40 ligand. Blood. 1998; 92: 2830–2843.

    Article  CAS  PubMed  Google Scholar 

  97. Alexandroff AB, Jackson AM & Paterson T, et al. Role for CD40–CD40 ligand interactions in the immune response to solid tumours. Mol Immunol. 2000; 37: 515–526.

    Article  CAS  PubMed  Google Scholar 

  98. Srinivasan A, Li F & Wong A, et al. Bcl-xL functions downstream of caspase-8 to inhibit Fas- and tumor necrosis factor receptor 1–induced apoptosis of MCF7 breast carcinoma cells. J Biol Chem. 1998; 273: 4523–4529.

    Article  CAS  PubMed  Google Scholar 

  99. Keane MM, Ettenberg SA & Lowrey GA, et al. Fas expression and function in normal and malignant breast cells lines. Cancer Res. 1996; 56: 4791–4798.

    CAS  PubMed  Google Scholar 

  100. Antonia SJ, Extermann M & Flavell RA . Immunologic nonresponsiveness to tumors. Crit Rev Oncol. 1998; 9: 35–41.

    Article  CAS  Google Scholar 

  101. Mackey MF, Gunn JR & Ting PP, et al. Protective immunity induced by tumor vaccines requires interaction between CD40 and its ligand, CD154. Cancer Res. 1997; 57: 2569–2574.

    CAS  PubMed  Google Scholar 

  102. van Mierlo GJ, den Boer AT & Medema JP, et al. CD40 stimulation leads to effective therapy of CD40(−) tumors through induction of strong systemic cytotoxic T lymphocyte immunity. Proc Natl Acad Sci USA. 2002; 99: 5561–5566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Courderc B, Zitvogel L & Douin-Echinard V, et al. Enhancement of antitumor immunity by expression of CD70 (CD27 ligand) or CD154 (CD40 ligand) costimulatory molecules in tumor cells. Cancer Gene Ther. 1998; 5: 163–175.

    Google Scholar 

  104. Ito D, Ogasawara K & Iwabuchi K, et al. Induction of CTL response by simultaneous administration of liposomal peptide vaccine with an anti-CD40 and anti-CTLA mAb. J Immunol. 2000; 164: 1230–1235.

    Article  CAS  PubMed  Google Scholar 

  105. Loskog A, Bjorkland A & Brown MP, et al. Potent antitumor effects of CD154 transduced tumor cells in experimental bladder cancer. J Urol. 2001; 166: 1093–1097.

    Article  CAS  PubMed  Google Scholar 

  106. Kikuchi T & Crystal RG . Anti-tumor immunity induced by in vivo adenovirus vector–mediated expression of CD40 ligand in tumor cells. Hum Gene Ther. 1999; 10: 1375–1387.

    Article  CAS  PubMed  Google Scholar 

  107. French RR, Chan HT, Tutt AL & Glennie MJ . CD40 antibody evokes a cytotoxic T cell response that eradicates lymphoma and bypasses T cell help. Nat Med. 1999; 5: 548–556.

    Article  CAS  PubMed  Google Scholar 

  108. Urashima M, Suzuki H & Yuza Y, et al. An oral CD40 ligand gene therapy against lymphoma using attenuated Salmonella typhimurium. Blood. 2000; 95: 1258–1263.

    Article  CAS  PubMed  Google Scholar 

  109. Todryk SM, Tutt AL & Green MHA, et al. CD40 ligation for immunotherapy of solid tumours. J Immunol Methods. 2001; 248: 139–147.

    Article  CAS  PubMed  Google Scholar 

  110. Esche C, Gambotto A & Satoh Y, et al. CD154 inhibits tumor-induced apoptosis in dendritic cells and tumor growth. Eur J Immunol. 1999; 29: 2148–2155.

    Article  CAS  PubMed  Google Scholar 

  111. Medema JP, Schuurhuis DH & Rea D, et al. Expression of the serpin serine protease inhibitor 6 protects dendritic cells against cytotoxic T lymphocyte–induced apoptosis. Differential modulation by T helper type 1 and type 2 cells. J Exp Med. 2001; 194: 657–668.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Kikuchi T, Moore MAS & Crystal RG . Dendritic cells modified to express CD40 ligand elicit therapeutic immunity against preexisting murine tumors. Blood. 2000; 96: 91–99.

    Article  CAS  PubMed  Google Scholar 

  113. Wurtzen PA, Nissen MH & Claesson MH . Maturation of dendritic cells by recombinant human CD40L-trimer leads to a homogeneous cell population with enhanced surface marker expression and increased cytokine production. Scand J Immunol. 2001; 53: 579–587.

    Article  CAS  PubMed  Google Scholar 

  114. Hoffman TK, Meidenbauer N & Muller-Berghaus J, et al. Proinflammatory cytokines and CD40 ligand enhance cross-presentation and cross-priming capability of human dendritic cells internalizing apoptotic cancer cells. J Immunother. 2001; 24: 162–171.

    Article  Google Scholar 

  115. Diehl L, den Boer AT & Schoenberger SP, et al. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T lymphocytes tolerance and augments anti-tumor vaccine efficacy. Nat Med. 1999; 5: 774–779.

    Article  CAS  PubMed  Google Scholar 

  116. Ridge JP, Di Rosa F & Matzinger P . A conditioned dendritic cell can be a temporal bridge between a CD4+ T-helper and a T-killer cell. Nature. 1998; 393: 474–478.

    Article  CAS  PubMed  Google Scholar 

  117. Bennett SR, Carbone FR & Karamlis F, et al. Help for cytotoxic T cell responses is mediated by CD40 signaling. Nature. 1998; 393: 478–486.

    Article  CAS  PubMed  Google Scholar 

  118. MacDonald AS, Straw AD, Bauman B & Pearce EJ . CD8-dendritic cell activation status plays an integral role in influencing TH2 response development. J Immunol. 2001; 167: 1982–1988.

    Article  CAS  PubMed  Google Scholar 

  119. De Becker G, Moulion V & Tielemnas F, et al. Regulation of T helper cell differentiation in vivo by soluble and membrane proteins provided by antigen-presenting cells. Eur J Immunol. 1998; 28: 3161–3171.

    Article  CAS  PubMed  Google Scholar 

  120. Terheyden P, Straten P & Brocker EB, et al. CD40-ligated dendritic cells effectively expand melanoma-specific CD8+ CTLs and CD4+ IFN-gamma–producing T cells from tumor-infiltrating lymphocytes. J Immunol. 2000; 164: 6633–6639.

    Article  CAS  PubMed  Google Scholar 

  121. MacDonald AS, Straw AD, Dalton NM & Pearce EJ . Cutting edge: Th2 response induction by dendritic cells: a role for CD40. J Immunol. 2002; 168: 537–540.

    Article  CAS  PubMed  Google Scholar 

  122. Jyothi MD & Khar A . Regulation of CD40L expression on natural killer cells by interleukin-12 and interferon gamma: its role in the elicitation of an effective antitumor immune response. Cancer Immunol Immunother. 2000; 49: 563–572.

    Article  CAS  PubMed  Google Scholar 

  123. Ranheim EA & Kipps TJ . Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal. J Exp Med. 1993; 177: 925–935.

    Article  CAS  PubMed  Google Scholar 

  124. Claxton DF, Kao SF & Ehmann C . CD40 ligand and IL-4 are required for optimal leukemic dendritic cell maturation (Abstract). Blood. 2001; 98: 589a

    Google Scholar 

  125. Kato K, Yoshida M & Takaue Y, et al. Retinoid and CD40 ligand cooperate to promote induction of immune accessory molecules and immune responses to human myeloid leukemia cells (Abstract). Blood. 2001; 98: 589a

    Google Scholar 

  126. Choudhury BA, Liang JC & Thomas EK, et al. Dendritic cells derived in vitro from acute myelogenous leukemia cells stimulate autologous, antileukemic T-cell responses. Blood. 1999; 93: 780–786.

    Article  CAS  PubMed  Google Scholar 

  127. Ghia P, Transidico P & Beiga JP, et al. Chemoattractants MDC and TARC are secreted by malignant B-cell precursors following CD40 ligation and support the migration of leukemia-specific T cells. Blood. 2001; 98: 533–540.

    Article  CAS  PubMed  Google Scholar 

  128. Dilloo D, Brown M & Roskrow M, et al. CD40 ligand induces an antileukemia immune response in vivo. Blood. 1997; 90: 1927–1933.

    Article  CAS  PubMed  Google Scholar 

  129. Cantwell MJ, Wierda WG & Lossos IS, et al. T cell activation following infection of primary follicle center lymphoma B cells with adenovirus encoding CD154. Leukemia. 2001; 15: 1451–1457.

    Article  CAS  PubMed  Google Scholar 

  130. Tolba KA, Bowers WJ & Hilchey SP, et al. Development of herpes simplex virus-1 amplicon-based immunotherapy for chronic lymphocytic leukemia. Blood. 2001; 98: 287–295.

    Article  CAS  PubMed  Google Scholar 

  131. Takahashi S, Rousseau RF & Yotnda P, et al. Autologous antileukemia immune response induced by chronic lymphocytic leukemia B cells expressing the CD40 ligand and interleukin 2 transgenes. Hum Gene Ther. 2001; 12: 659–670.

    Article  CAS  PubMed  Google Scholar 

  132. Takahashi S, Yotnda P & Rousseau RF, et al. Transgenic expression of CD40L and interleukin-2 induces an autologous anti-tumor immune response in patients with non-Hodgkin's lymphoma. Cancer Gene Ther. 2001; 8: 378–387.

    Article  CAS  PubMed  Google Scholar 

  133. Biagi E, Rousseau RF & Yvon E, et al. CD40-activated, IL-2 transduced chronic lymphocytic leukemia B cells (B-CLL) express high levels of CD40L, B7-1, and B7-2: feasibility for immunotherapy of CLL (Abstract). Cancer Res. 2002; 43: 557

    Google Scholar 

  134. Liu Y, Qureshi M & Xiang J . Antitumor immune responses derived from transgenic expression of CD40 ligand in myeloma cells. Cancer Biother Radiopharm. 2002; 17: 11–18.

    Article  PubMed  Google Scholar 

  135. Dotti G, Savoldo B & Takahashi S, et al. Adenovector-induced expression of human-CD40-ligand (hCD40L) by multiple myeloma cells. A model for immunotherapy. Exp Hematol. 2001; 29: 952–961.

    Article  CAS  PubMed  Google Scholar 

  136. Noguchi M, Imaizumi K & Kawabe T, et al. Induction of antitumor immunity by transduction of CD40 ligand gene and interferon-gamma into lung cancer. Cancer Gene Ther. 2001; 8: 421–429.

    Article  CAS  PubMed  Google Scholar 

  137. Schmitz V, Barajas M & Wang L, et al. Adenovirus-mediated CD40 ligand gene therapy in a rat model of orthotopic hepatocellular carcinoma. Hepatology. 2001; 34: 72–81.

    Article  CAS  PubMed  Google Scholar 

  138. Nakajima A, Kodama T & Morimoto S, et al. Antitumor effect of CD40 ligand: elicitation of local and systemic antitumor responses by IL-12 and B7. J Immunol. 1998; 161: 1901–1907.

    CAS  PubMed  Google Scholar 

  139. Gurunathan S, Irvine KR & Wu CY, et al. CD40 ligand/trimer DNA enhances both humoral and cellular immune responses and induces protective immunity to infections and tumor challenge. J Immunol. 1998; 161: 4563–4571.

    CAS  PubMed  Google Scholar 

  140. Vonderheide RH, Dutcher JP & Anderson JE, et al. Phase I study of recombinant human CD40 ligand in cancer patients. J Clin Oncol. 2001; 19: 3280–3287.

    Article  CAS  PubMed  Google Scholar 

  141. Younes A . CD40 ligand therapy of lymphoma patients. J Clin Oncol. 2001; 19: 4351–4353.

    Article  CAS  PubMed  Google Scholar 

  142. Felzmann T, Buchberger M & Lehner M, et al. Functional maturation of dendritic cells by exposure to CD40L transgenic tumor cells, fibroblasts or keratinocytes. Cancer Lett. 2001; 68: 145–154.

    Article  Google Scholar 

  143. Kedl RM, Jordan M & Potter T, et al. CD40 stimulation accelerates deletion of tumor-specific CD8+ T cells in the absence of tumor-antigen vaccination. Pro Natl Acad Sci USA. 2001; 98: 10811–10816.

    Article  CAS  Google Scholar 

  144. Batrla R, Linnebacher M & Rudy W, et al. CD40-expressing carcinoma cells induce down-regulation of CD40 ligand (CD154) and impair T-cell functions. Cancer Res. 2002; 62: 2052–2057.

    CAS  PubMed  Google Scholar 

  145. Fidler IJ . Seed and soil revisited: contribution of the organ microenvironment to cancer metastasis. Surg Oncol Clin North Am. 2001; 10: 257–269.

    Article  CAS  Google Scholar 

  146. Brown MP, Topham DJ & Sangster MJ, et al. Thymic lymphoproliferative disease after successful correction of CD40 ligand deficiency by gene transfer in mice. Nat Med. 1998; 4: 1253–1260.

    Article  CAS  PubMed  Google Scholar 

  147. Dunn RJ, Luedecker CJ & Haugen HS, et al. Thymic overexpression of CD40 ligand disrupts normal thymic epithelial organization. J Histochem Cytochem. 1997; 45: 129–141.

    Article  CAS  PubMed  Google Scholar 

  148. Kato K, Cantewell MJ, Sharma S & Kipps TJ . Gene transfer of CD40 ligand induces autologous immune recognition of chronic lymphocytic leukemia B cells. J Clin Invest. 1998; 101: 1133–1140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Wierda WG, Cantwell MJ & Woods SJ, et al. CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia. Blood. 2000; 96: 2917–2924.

    Article  CAS  PubMed  Google Scholar 

  150. Anether G, Marschitz I, Tinhofer I & Greil R . Interleukin-15 as a potential costimulatory cytokine in CD154 gene therapy of chronic lymphocytic leukemia. Blood. 2002; 99: 722–723.

    Article  CAS  PubMed  Google Scholar 

  151. Kipps TJ, Chu P & Wierda WG . Immunogenetic therapy for B cell malignancies. Semin Oncol. 2000; 27 (Suppl 12): 104–109.

    CAS  PubMed  Google Scholar 

  152. Schultze JL, Anderson KC & Gilleece MH, et al. A pilot study of combined immunotherapy with autologous adoptive tumor-specific T cell transfer, vaccination with CD40-activated malignant B cells and interleukin 2. Br J Haematol. 2001; 113: 455–460.

    Article  CAS  PubMed  Google Scholar 

  153. Hernandez-Alcoceba R, Pihalja M, Wicha MS & Clarke MF . A novel, conditionally replicative adenovirus for the treatment of breast cancer that allows controlled replication of E1a-deleted adenoviral vectors. Hum Gene Ther. 2000; 11: 2009–2024.

    Article  CAS  PubMed  Google Scholar 

  154. Pirskhalaishvili G, Shurin GV & Esche C, et al. Cytokine-mediated protection of human dendritic cells from prostate cancer-induced apoptosis is regulated by the Bcl-2 family of proteins. Br J Cancer. 2000; 83: 506–513.

    Article  Google Scholar 

  155. Nemunaitis J, Cunningham C & Buchanan A, et al. Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility, and biological activity. Gene Ther. 2001; 8: 746–759.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported, in part, by the Robert Shanbaum Memorial Fund, the James E Nauss Cancer Research Fund, the Summerfield Roberts Grant, the Edward and Ruth Wilkof Foundation, and the Tri Delta Cancer Research Fund.

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  1. Cancer Immunology Research Laboratory, Baylor Sammons Cancer Center, Baylor University Medical Center, Dallas, 75246, Texas, USA

    Alex W Tong & Marvin J Stone

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Tong, A., Stone, M. Prospects for CD40-directed experimental therapy of human cancer. Cancer Gene Ther 10, 1–13 (2003). https://doi.org/10.1038/sj.cgt.7700527

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