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Journal of Biomedicine and Biotechnology
Volume 2010 (2010), Article ID 752381, 12 pages
http://dx.doi.org/10.1155/2010/752381
Review Article

Antigen-Specific Polyclonal Cytotoxic T Lymphocytes Induced by Fusions of Dendritic Cells and Tumor Cells

1Division of Gastroenterology and Hepatology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo 105-8461, Japan
2Institute of Clinical Medicine and Research, The Jikei University School of Medicine, Tokyo 105-8461, Japan
3Saitama Cancer Center Research Institute for Clinical Oncology, 818 Komuro, Ina-machi, Kitaadachi-gun, Saitama 362-0806, Japan
4Department of Medicine, Boston University School of Medicine, 650 Albany Street, Room 309, Boston, MA 02118, USA

Received 29 November 2009; Revised 21 January 2010; Accepted 1 February 2010

Academic Editor: Zhengguo Xiao

Copyright © 2010 Shigeo Koido et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. R. M. Steinman and J. Banchereau, “Taking dendritic cells into medicine,” Nature, vol. 449, no. 7161, pp. 419–426, 2007. View at Publisher · View at Google Scholar · View at PubMed
  2. J. Banchereau and A. K. Palucka, “Dendritic cells as therapeutic vaccines against cancer,” Nature Reviews Immunology, vol. 5, no. 4, pp. 296–306, 2005. View at Publisher · View at Google Scholar · View at PubMed
  3. J. Banchereau and R. M. Steinman, “Dendritic cells and the control of immunity,” Nature, vol. 392, no. 6673, pp. 245–252, 1998. View at Publisher · View at Google Scholar · View at PubMed
  4. A. Mackensen, B. Herbst, J.-L. Chen, et al., “Phase I study in melanoma patients of a vaccine with peptide-pulsed dendritic cells generated in vitro from CD34+ hematopoietic progenitor cells,” International Journal of Cancer, vol. 89, no. 2, pp. 385–392, 2000.
  5. B. Thurner, I. Haendle, C. Roder, et al., “Vaccination with Mage-3A1 peptide-pulsed nature, monocyte-derived dendritic cells expands specific cytotoxic T cells and induces regression of some metastases in advanced stage IV melanoma,” Journal of Experimental Medicine, vol. 190, no. 11, pp. 1669–1678, 1999. View at Publisher · View at Google Scholar
  6. C. M. Celluzzi, J. I. Mayordomo, W. J. Storkus, M. T. Lotze, and L. D. Falo Jr., “Peptide-pulsed dendritic cells induce antigen-specific, CTL-mediated protective tumor immunity,” Journal of Experimental Medicine, vol. 183, no. 1, pp. 283–287, 1996. View at Publisher · View at Google Scholar
  7. F. O. Nestle, S. Alijagic, M. Gilliet, et al., “Vaccination of melanoma patients with peptide- or tumor lysate-pulsed dendritic cells,” Nature Medicine, vol. 4, no. 3, pp. 328–332, 1998. View at Publisher · View at Google Scholar
  8. J. I. Mayordomo, T. Zorina, W. J. Storkus, et al., “Bone marrow-derived dendritic cells pulsed with synthetic tumour peptides elicit protective and therapeutic antitumour immunity,” Nature Medicine, vol. 1, no. 12, pp. 1297–1302, 1995.
  9. J. Gong, L. Chen, D. Chen, et al., “Induction of antigen-specific antitumor immunity with adenovirus-transduced dendritic cells,” Gene Therapy, vol. 4, no. 10, pp. 1023–1028, 1997.
  10. S. Koido, M. Kashiwaba, D. Chen, S. Gendler, D. Kufe, and J. Gong, “Induction of antitumor immunity by vaccination of dendritic cells transfected with MUC1 RNA,” The Journal of Immunology, vol. 165, no. 10, pp. 5713–5719, 2000.
  11. K. Shimizu, H. Kuriyama, J. Kjaergaard, W. Lee, H. Tanaka, and S. Shu, “Comparative analysis of antigen loading strategies of dendritic cells for tumor immunotherapy,” Journal of Immunotherapy, vol. 27, no. 4, pp. 265–272, 2004.
  12. J. Gong, D. Chen, M. Kashiwaba, and D. Kufe, “Induction of antitumor activity by immunization with fusions of dendritic and carcinoma cells,” Nature Medicine, vol. 3, no. 5, pp. 558–561, 1997.
  13. J. Gong, S. Koido, and S. K. Calderwood, “Cell fusion: from hybridoma to dendritic cell-based vaccine,” Expert Review of Vaccines, vol. 7, no. 7, pp. 1055–1068, 2008. View at Publisher · View at Google Scholar · View at PubMed
  14. S. Koido, E. Hara, S. Homma, K. Fujise, J. Gong, and H. Tajiri, “Dendritic/tumor fusion cell-based vaccination against cancer,” Archivum Immunologiae et Therapiae Experimentalis, vol. 55, no. 5, pp. 281–287, 2007. View at Publisher · View at Google Scholar
  15. S. Koido, E. Hara, S. Homma, T. Ohkusa, J. Gong, and H. Tajiri, “Cancer immunotherapy by fusions of dendritic cells and tumor cells,” Immunotherapy, vol. 1, no. 1, pp. 49–62, 2009.
  16. H. Tanaka, K. Shimizu, T. Hayashi, and S. Shu, “Therapeutic immune response induced by electrofusion of dendritic and tumor cells,” Cellular Immunology, vol. 220, no. 1, pp. 1–12, 2002. View at Publisher · View at Google Scholar
  17. K. Hiraoka, S. Yamamoto, S. Otsuru, et al., “Enhanced tumor-specific long-term immunity of hemagglutinating virus of Japan-mediated dendritic cell-tumor fused cell vaccination by coadministration with CpG oligodeoxynucleotides,” The Journal of Immunology, vol. 173, no. 7, pp. 4297–4307, 2004.
  18. S. Koido, E. Hara, S. Homma, et al., “Streptococcal preparation OK-432 promotes fusion efficiency and enhances induction of antigen-specific CTL by fusions of dendritic cells and colorectal cancer cells,” The Journal of Immunology, vol. 178, no. 1, pp. 613–622, 2007.
  19. J. Li, L. M. Holmes, K. J. Franek, K. E. Burgin, T. E. Wagner, and Y. Wei, “Purified hybrid cells from dendritic cell and tumor cell fusions are superior activators of antitumor immunity,” Cancer Immunology, Immunotherapy, vol. 50, no. 9, pp. 456–462, 2001. View at Publisher · View at Google Scholar
  20. T. Suzuki, T. Fukuhara, M. Tanaka, et al., “Vaccination of dendritic cells loaded with interleukin-12-secreting cancer cells augments in vivo antitumor immunity: characteristics of syngeneic and allogeneic antigen-presenting cell cancer hybrid cells,” Clinical Cancer Research, vol. 11, no. 1, pp. 58–66, 2005.
  21. D. Avigan, B. Vasir, J. Gong, et al., “Fusion cell vaccination of patients with metastatic breast and renal cancer induces immunological and clinical responses,” Clinical Cancer Research, vol. 10, no. 14, pp. 4699–4708, 2004. View at Publisher · View at Google Scholar · View at PubMed
  22. D. E. Avigan, B. Vasir, D. J. George, et al., “Phase I/II study of vaccination with electrofused allogeneic dendritic cells/autologous tumor-derived cells in patients with stage IV renal cell carcinoma,” Journal of Immunotherapy, vol. 30, no. 7, pp. 749–761, 2007. View at Publisher · View at Google Scholar · View at PubMed
  23. M. C. Wolkers, N. Brouwenstijn, A. H. Bakker, M. Toebes, and T. N. M. Schumacher, “Antigen bias in T cell cross-priming,” Science, vol. 304, no. 5675, pp. 1314–1317, 2004. View at Publisher · View at Google Scholar · View at PubMed
  24. J. Wang, S. Saffold, X. Cao, J. Krauss, and W. Chen, “Eliciting T cell immunity against poorly immunogenic tumors by immunization with dendritic cell-tumor fusion vaccines,” The Journal of Immunology, vol. 161, no. 10, pp. 5516–5524, 1998.
  25. F. Benencia, M. C. Courreges, and G. Coukos, “Whole tumor antigen vaccination using dendritic cells: comparison of RNA electroporation and pulsing with UV-irradiated tumor cells,” Journal of Translational Medicine, vol. 6, article 21, 2008. View at Publisher · View at Google Scholar · View at PubMed
  26. S. Shu, R. Zheng, W. T. Lee, and P. A. Cohen, “Immunogenicity of dendritic-tumor fusion hybrids and their utility in cancer immunotherapy,” Critical Reviews in Immunology, vol. 27, no. 5, pp. 463–483, 2007.
  27. S. Koido, M. Ohana, C. Liu, et al., “Dendritic cells fused with human cancer cells: morphology, antigen expression, and T cell stimulation,” Clinical Immunology, vol. 113, no. 3, pp. 261–269, 2004. View at Publisher · View at Google Scholar · View at PubMed
  28. M. Okamoto, S. Furuichi, Y. Nishioka, et al., “Expression of toll-like receptor 4 on dendritic cells is significant for anticancer effect of dendritic cell-based immunotherapy in combination with active component of OK-432, a streptococcal preparation,” Cancer Research, vol. 64, no. 15, pp. 5461–5470, 2004.
  29. C. C. Norbury, S. Basta, K. B. Donohue, et al., “CD8+ T cell cross-priming via transfer of proteasome substrates,” Science, vol. 304, no. 5675, pp. 1318–1321, 2004. View at Publisher · View at Google Scholar · View at PubMed
  30. S. Koido, E. Hara, S. Homma, et al., “Synergistic induction of antigen-specific CTL by fusions of TLR-stimulated dendritic cells and heat-stressed tumor cells,” The Journal of Immunology, vol. 179, no. 7, pp. 4874–4883, 2007.
  31. S. Patton, S. J. Gendler, and A. P. Spicer, “The epithelial mucin, MUC1, of milk, mammary gland and other tissues,” Biochimica et Biophysica Acta, vol. 1241, no. 3, pp. 407–423, 1995. View at Publisher · View at Google Scholar
  32. G. J. Rowse, R. M. Tempero, M. L. VanLith, M. A. Hollingsworth, and S. J. Gendler, “Tolerance and immunity to MUC1 in a human MUC1 transgenic murine model,” Cancer Research, vol. 58, no. 2, pp. 315–321, 1998.
  33. J. Gong, D. Chen, M. Kashiwaba, et al., “Reversal of tolerance to human MUC1 antigen in MUC1 transgenic mice immunized with fusions of dendritic and carcinoma cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 11, pp. 6279–6283, 1998. View at Publisher · View at Google Scholar
  34. S. Koido, Y. Tanaka, D. Chen, D. Kufe, and J. Gong, “The kinetics of in vivo priming of CD4 and CD8 T cells by dendritic/tumor fusion cells in MUC1-transgenic mice,” The Journal of Immunology, vol. 168, no. 5, pp. 2111–2117, 2002.
  35. Y. Tanaka, S. Koido, D. Chen, S. J. Gendler, D. Kufe, and J. Gong, “Vaccination with allogeneic dendritic cells fused to carcinoma cells induces antitumor immunity in MUC1 transgenic mice,” Clinical Immunology, vol. 101, no. 2, pp. 192–200, 2001. View at Publisher · View at Google Scholar · View at PubMed
  36. X. Cao, W. Zhang, J. Wang, et al., “Therapy of established tumour with a hybrid cellular vaccine generated by using granulocyte-macrophage colony-stimulating factor genetically modified dendritic cells,” Immunology, vol. 97, no. 4, pp. 616–625, 1999. View at Publisher · View at Google Scholar
  37. S. Salomskaite-Davalgiene, K. Cepurniene, S. Satkauskas, M. S. Venslauskas, and L. M. Mir, “Extent of cell electrofusion in vitro and in vivo is cell line dependent,” Anticancer Research, vol. 29, no. 8, pp. 3125–3130, 2009.
  38. R. Zheng, P. A. Cohen, C. A. Paustian, et al., “Paired toll-like receptor agonists enhance vaccine therapy through induction of interleukin-12,” Cancer Research, vol. 68, no. 11, pp. 4045–4049, 2008. View at Publisher · View at Google Scholar · View at PubMed
  39. H. Kuriyama, S. Watanabe, J. Kjaergaard, et al., “Mechanism of third signals provided by IL-12 and OX-40R ligation in eliciting therapeutic immunity following dendritic-tumor fusion vaccination,” Cellular Immunology, vol. 243, no. 1, pp. 30–40, 2006. View at Publisher · View at Google Scholar · View at PubMed
  40. V. Phan, F. Errington, S. C. Cheong, et al., “A new genetic method to generate and isolate small, short-lived but highly potent dendritic cell-tumor cell hybrid vaccines,” Nature Medicine, vol. 9, no. 9, pp. 1215–1219, 2003. View at Publisher · View at Google Scholar · View at PubMed
  41. J. Gong, V. Apostolopoulos, D. Chen, et al., “Selection and characterization of MUC1-specific CD8+ T cells from MUC1 transgenic mice immunized with dendritic-carcinoma fusion cells,” Immunology, vol. 101, no. 3, pp. 316–324, 2000. View at Publisher · View at Google Scholar
  42. J. Y. Kao, Y. Gong, C.-M. Chen, Q.-D. Zheng, and J.-J. Chen, “Tumor-derived TGF-β reduces the efficacy of dendritic cell/tumor fusion vaccine,” The Journal of Immunology, vol. 170, no. 7, pp. 3806–3811, 2003.
  43. T. Iinuma, S. Homma, T. Noda, D. Kufe, T. Ohno, and G. Toda, “Prevention of gastrointestinal tumors based on adenomatous polyposis coli gene mutation by dendritic cell vaccine,” Journal of Clinical Investigation, vol. 113, no. 9, pp. 1307–1317, 2004. View at Publisher · View at Google Scholar
  44. J. Y. Kao, M. Zhang, C.-M. Chen, and J.-J. Chen, “Superior efficacy of dendritic cell-tumor fusion vaccine compared with tumor lysate-pulsed dendritic cell vaccine in colon cancer,” Immunology Letters, vol. 101, no. 2, pp. 154–159, 2005. View at Publisher · View at Google Scholar · View at PubMed
  45. F. Xu, Y.-J. Ye, Z.-R. Cui, and S. Wang, “Allogeneic dendritomas induce anti-tumour immunity against metastatic colon cancer,” Scandinavian Journal of Immunology, vol. 61, no. 4, pp. 364–369, 2005. View at Publisher · View at Google Scholar · View at PubMed
  46. T. Yasuda, T. Kamigaki, T. Nakamura, et al., “Dendritic cell-tumor cell hybrids enhance the induction of cytotoxic T lymphocytes against murine colon cancer: a comparative analysis of antigen loading methods for the vaccination of immunotherapeutic dendritic cells,” Oncology Reports, vol. 16, no. 6, pp. 1317–1324, 2006.
  47. T. Yasuda, T. Kamigaki, K. Kawasaki, et al., “Superior anti-tumor protection and therapeutic efficacy of vaccination with allogeneic and semiallogeneic dendritic cell/tumor cell fusion hybrids for murine colon adenocarcinoma,” Cancer Immunology, Immunotherapy, vol. 56, no. 7, pp. 1025–1036, 2007. View at Publisher · View at Google Scholar · View at PubMed
  48. A. Ishida, H. Tanaka, T. Hiura, et al., “Generation of anti-tumour effector T cells from naive T cells by stimulation with dendritic/tumour fusion cells,” Scandinavian Journal of Immunology, vol. 66, no. 5, pp. 546–554, 2007. View at Publisher · View at Google Scholar · View at PubMed
  49. J. Gong, D. Avigan, D. Chen, et al., “Activation of antitumor cytotoxic T lymphocytes by fusions of human dendritic cells and breast carcinoma cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 6, pp. 2715–2718, 2000. View at Publisher · View at Google Scholar · View at PubMed
  50. J. Xia, Y. Tanaka, S. Koido, et al., “Prevention of spontaneous breast carcinoma by prophylactic vaccination with dendritic/tumor fusion cells,” The Journal of Immunology, vol. 170, no. 4, pp. 1980–1986, 2003.
  51. D. Chen, J. Xia, Y. Tanaka, et al., “Immunotherapy of spontaneous mammary carcinoma with fusions of dendritic cells and mucin 1-positive carcinoma cells,” Immunology, vol. 109, no. 2, pp. 300–307, 2003. View at Publisher · View at Google Scholar
  52. M. Zhang, B. E. Berndt, J. J. Chen, and J. Y. Kao, “Expression of a soluble TGF-beta receptor by tumor cells enhances dendritic cell/tumor fusion vaccine efficacy,” The Journal of Immunology, vol. 181, no. 5, pp. 3690–3697, 2008.
  53. H. Tamai, S. Watanabe, R. Zheng, et al., “Effective treatment of spontaneous metastases derived from a poorly immunogenic murine mammary carcinoma by combined dendritic-tumor hybrid vaccination and adoptive transfer of sensitized T cells,” Clinical Immunology, vol. 127, no. 1, pp. 66–77, 2008. View at Publisher · View at Google Scholar · View at PubMed
  54. G.-H. Guo, S.-Z. Chen, J. Yu, et al., “In vivo anti-tumor effect of hybrid vaccine of dendritic cells and esophageal carcinoma cells on esophageal carcinoma cell line 109 in mice with severe combined immune deficiency,” World Journal of Gastroenterology, vol. 14, no. 8, pp. 1167–1174, 2008. View at Publisher · View at Google Scholar
  55. M. Yamamoto, T. Kamigaki, K. Yamashita, et al., “Enhancement of anti-tumor immunity by high levels of Th1 and Th17 with a combination of dendritic cell fusion hybrids and regulatory T cell depletion in pancreatic cancer,” Oncology Reports, vol. 22, no. 2, pp. 337–343, 2009. View at Publisher · View at Google Scholar
  56. S. Homma, G. Toda, J. Gong, D. Kufe, and T. Ohno, “Preventive antitumor activity against hepatocellular carcinoma (HCC) induced by immunization with fusions of dendritic cells and HCC cells in mice,” Journal of Gastroenterology, vol. 36, no. 11, pp. 764–771, 2001. View at Publisher · View at Google Scholar
  57. J.-K. Zhang, J. Li, J. Zhang, H.-B. Chen, and S.-B. Chen, “Antitumor immunopreventive and immunotherapeutic effect in mice induced by hybrid vaccine of dendritic cells and hepatocarcinoma in vivo,” World Journal of Gastroenterology, vol. 9, no. 3, pp. 479–484, 2003.
  58. M. Iriei, S. Homma, H. Komita, et al., “Inhibition of spontaneous development of liver tumors by inoculation with dendritic cells loaded with hepatocellular carcinoma cells in C3H/HeNCRJ mice,” International Journal of Cancer, vol. 111, no. 2, pp. 238–245, 2004. View at Publisher · View at Google Scholar · View at PubMed
  59. H.-M. Zhang, L.-W. Zhang, W.-C. Liu, J. Cheng, X.-M. Si, and J. Ren, “Comparative analysis of DC fused with tumor cells or transfected with tumor total RNA as potential cancer vaccines against hepatocellular carcinoma,” Cytotherapy, vol. 8, no. 6, pp. 580–588, 2006. View at Publisher · View at Google Scholar · View at PubMed
  60. X.-L. Sheng and H. Zhang, “In-vitro activation of cytotoxic T lymphocytes by fusion of mouse hepatocellular carcinoma cells and lymphotactin gene-modified dendritic cells,” World Journal of Gastroenterology, vol. 13, no. 44, pp. 5944–5950, 2007.
  61. C. M. Celluzzi and L. D. Falo Jr., “Physical interaction between dendritic cells and tumor cells results in an immunogen that induces protective and therapeutic tumor rejection,” The Journal of Immunology, vol. 160, no. 7, pp. 3081–3085, 1998.
  62. R. Savai, R. T. Schermuly, M. Schneider, et al., “Hybrid-primed lymphocytes and hybrid vaccination prevent tumor growth of Lewis lung carcinoma in mice,” Journal of Immunotherapy, vol. 29, no. 2, pp. 175–187, 2006. View at Publisher · View at Google Scholar · View at PubMed
  63. J. B. Weise, S. Maune, T. Gorogh, et al., “A dendritic cell based hybrid cell vaccine generated by electrofusion for immunotherapy strategies in HNSCC,” Auris Nasus Larynx, vol. 31, no. 2, pp. 149–153, 2004. View at Publisher · View at Google Scholar · View at PubMed
  64. W. M. Siders, K. L. Vergilis, C. Johnson, J. Shields, and J. M. Kaplan, “Induction of specific antitumor immunity in the mouse with the electrofusion product of tumor cells and dendritic cells,” Molecular Therapy, vol. 7, no. 4, pp. 498–505, 2003. View at Publisher · View at Google Scholar
  65. J. Kjaergaard, K. Shimizu, and S. Shu, “Electrofusion of syngeneic dendritic cells and tumor generates potent therapeutic vaccine,” Cellular Immunology, vol. 225, no. 2, pp. 65–74, 2003. View at Publisher · View at Google Scholar
  66. W. Guo, Y. Guo, S. Tang, H. Qu, and H. Zhao, “Dendritic cell-Ewing's sarcoma cell hybrids enhance antitumor immunity,” Clinical Orthopaedics and Related Research, vol. 466, no. 9, pp. 2176–2183, 2008. View at Publisher · View at Google Scholar · View at PubMed
  67. H. Matsue, K. Matsue, D. Edelbaum, M. Walters, A. Morita, and A. Takashima, “New strategy for efficient selection of dendritic cell-tumor hybrids and clonal heterogeneity of resulting hybrids,” Cancer Biology and Therapy, vol. 3, no. 11, pp. 1145–1151, 2004.
  68. J. Gong, S. Koido, D. Chen, et al., “Immunization against murine multiple myeloma with fusions of dendritic and plasmacytoma cells is potentiated by interleukin 12,” Blood, vol. 99, no. 7, pp. 2512–2517, 2002. View at Publisher · View at Google Scholar
  69. Y. Liu, W. Zhang, T. Chan, A. Saxena, and J. Xiang, “Engineered fusion hybrid vaccine of IL-4 gene-modified myeloma and relative mature dendritic cells enhances antitumor immunity,” Leukemia Research, vol. 26, no. 8, pp. 757–763, 2002. View at Publisher · View at Google Scholar
  70. S. Hao, X. Bi, S. Xu, et al., “Enhanced antitumor immunity derived from a novel vaccine of fusion hybrid between dendritic and engineered myeloma cells,” Experimental Oncology, vol. 26, no. 4, pp. 300–306, 2004.
  71. M. Shi, L. Su, S. Hao, X. Guo, and J. Xiang, “Fusion hybrid of dendritic cells and engineered tumor cells expressing interleukin-12 induces type 1 immune responses against tumor,” Tumori, vol. 91, no. 6, pp. 531–538, 2005.
  72. S. Queant, C.-O. Sarde, M.-G. Gobert, J. Kadouche, and A. Roseto, “Antitumor response against myeloma cells by immunization with mouse syngenic dendritoma,” Hybridoma, vol. 24, no. 4, pp. 182–188, 2005.
  73. D. Xia, F. Li, and J. Xiang, “Engineered fusion hybrid vaccine of IL-18 gene-modified tumor cells and dendritic cells induces enhanced antitumor immunity,” Cancer Biotherapy and Radiopharmaceuticals, vol. 19, no. 3, pp. 322–330, 2004. View at Publisher · View at Google Scholar · View at PubMed
  74. L. Lespagnard, P. Mettens, A.-M. Verheyden, et al., “Dendritic cells fused with mastocytoma cells elicit therapeutic antitumor immunity,” International Journal of Cancer, vol. 76, no. 2, pp. 250–258, 1998. View at Publisher · View at Google Scholar
  75. H. Iinuma, K. Okinaga, R. Fukushima, et al., “Superior protective and therapeutic effects of IL-12 and IL-18 gene-transduced dendritic neuroblastoma fusion cells on liver metastasis of murine neuroblastoma,” The Journal of Immunology, vol. 176, no. 6, pp. 3461–3469, 2006.
  76. C. T. Guy, R. D. Cardiff, and W. J. Muller, “Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease,” Molecular and Cellular Biology, vol. 12, no. 3, pp. 954–961, 1992.
  77. Y. Tanaka, S. Koido, M. Ohana, C. Liu, and J. Gong, “Induction of impaired antitumor immunity by fusion of MHC class II-deficient dendritic cells with tumor cells,” The Journal of Immunology, vol. 174, no. 3, pp. 1274–1280, 2005.
  78. R. E. M. Toes, F. Ossendorp, R. Offringa, and C. J. M. Melief, “CD4 T cells and their role in antitumor immune responses,” Journal of Experimental Medicine, vol. 189, no. 5, pp. 753–756, 1999. View at Publisher · View at Google Scholar
  79. S. P. Schoenberger, R. E. M. Toes, E. I. H. van der Voort, R. Offringa, and C. J. M. Melief, “T-cell help for cytotoxic T lymphocytes is mediated by CD40-CD40L interactions,” Nature, vol. 393, no. 6684, pp. 480–483, 1998.
  80. E. R. Fearon, D. M. Pardoll, T. Itaya, et al., “Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response,” Cell, vol. 60, no. 3, pp. 397–403, 1990. View at Publisher · View at Google Scholar
  81. K. Hung, R. Hayashi, A. Lafond-Walker, C. Lowenstein, D. Pardoll, and H. Levitsky, “The central role of CD4+ T cells in the antitumor immune response,” Journal of Experimental Medicine, vol. 188, no. 12, pp. 2357–2368, 1998. View at Publisher · View at Google Scholar
  82. K. Schepers, M. Toebes, G. Sotthewes, et al., “Differential kinetics of antigen-specific CD4+ and CD8+ T cell responses in the regression of retrovirus-induced sarcomas,” The Journal of Immunology, vol. 169, no. 6, pp. 3191–3199, 2002.
  83. F. Ossendorp, E. Mengede, M. Camps, R. Filius, and C. J. M. Melief, “Specific T helper cell requirement for optimal induction of cytotoxic T lymphocytes against major histocompatibility complex class II negative tumors,” Journal of Experimental Medicine, vol. 187, no. 5, pp. 693–702, 1998. View at Publisher · View at Google Scholar
  84. S. Koido, E. Hara, A. Torii, et al., “Induction of antigen-specific CD4- and CD8-mediated T-cell responses by fusions of autologous dendritic cells and metastatic colorectal cancer cells,” International Journal of Cancer, vol. 117, no. 4, pp. 587–595, 2005. View at Publisher · View at Google Scholar · View at PubMed
  85. S. R. M. Bennett, F. R. Carbone, F. Karamalis, J. F. A. P. Miller, and W. R. Heath, “Induction of a CD8+ cytotoxic T lymphocyte response by cross-priming requires cognate CD4+ T cell help,” Journal of Experimental Medicine, vol. 186, no. 1, pp. 65–70, 1997. View at Publisher · View at Google Scholar
  86. W. R. Heath and F. R. Carbone, “Cross-presentation in viral immunity and self-tolerance,” Nature Reviews Immunology, vol. 1, no. 2, pp. 126–134, 2001.
  87. E. Celis, “Toll-like receptor ligands energize peptide vaccines through multiple paths,” Cancer Research, vol. 67, no. 17, pp. 7945–7947, 2007. View at Publisher · View at Google Scholar · View at PubMed
  88. S. Koido, S. Homma, E. Hara, et al., “In vitro generation of cytotoxic and regulatory T cells by fusions of human dendritic cells and hepatocellular carcinoma cells,” Journal of Translational Medicine, vol. 6, article 51, 2008. View at Publisher · View at Google Scholar · View at PubMed
  89. R.-F. Wang, “Regulatory T cells and toll-like receptors in cancer therapy,” Cancer Research, vol. 66, no. 10, pp. 4987–4990, 2006. View at Publisher · View at Google Scholar · View at PubMed
  90. R.-F. Wang, Y. Miyahara, and H. Y. Wang, “Toll-like receptors and immune regulation: implications for cancer therapy,” Oncogene, vol. 27, no. 2, pp. 181–189, 2008. View at Publisher · View at Google Scholar · View at PubMed
  91. M. Chen, L. Huang, and J. Wang, “Deficiency of Bim in dendritic cells contributes to overactivation of lymphocytes and autoimmunity,” Blood, vol. 109, no. 10, pp. 4360–4367, 2007. View at Publisher · View at Google Scholar · View at PubMed
  92. Y. Tamura, P. Peng, K. Liu, M. Daou, and P. K. Srivastava, “Immunotherapy of tumors with autologous tumor-derived heat shock protein preparations,” Science, vol. 278, no. 5335, pp. 117–120, 1997. View at Publisher · View at Google Scholar
  93. Y. Enomoto, A. Bharti, A. A. Khaleque, et al., “Enhanced immunogenicity of heat shock protein 70 peptide complexes from dendritic cell-tumor fusion cells,” The Journal of Immunology, vol. 177, no. 9, pp. 5946–5955, 2006.
  94. J. Gong, Y. Zhang, J. Durfee, et al., “A heat shock protein 70-based vaccine with enhanced immunogenicity for clinical use,” The Journal of Immunology, vol. 184, no. 1, pp. 488–496, 2010.
  95. S. Koido, E. Hara, S. Homma, et al., “Dendritic cells fused with allogeneic colorectal cancer cell line present multiple colorectal cancer-specific antigens and induce antitumor immunity against autologous tumor cells,” Clinical Cancer Research, vol. 11, no. 21, pp. 7891–7900, 2005. View at Publisher · View at Google Scholar · View at PubMed
  96. S. Koido, Y. Tanaka, H. Tajiri, and J. Gong, “Generation and functional assessment of antigen-specific T cells stimulated by fusions of dendritic cells and allogeneic breast cancer cells,” Vaccine, vol. 25, no. 14, pp. 2610–2619, 2007. View at Publisher · View at Google Scholar · View at PubMed
  97. A. R. Neves, L. F. C. Ensina, L. B. Anselmo, et al., “Dendritic cells derived from metastatic cancer patients vaccinated with allogeneic dendritic cell-autologous tumor cell hybrids express more CD86 and induce higher levels of interferon-gamma in mixed lymphocyte reactions,” Cancer Immunology, Immunotherapy, vol. 54, no. 1, pp. 61–66, 2005. View at Publisher · View at Google Scholar · View at PubMed
  98. U. Trefzer, G. Herberth, K. Wohlan, et al., “Tumour-dendritic hybrid cell vaccination for the treatment of patients with malignant melanoma: immunological effects and clinical results,” Vaccine, vol. 23, no. 17-18, pp. 2367–2373, 2005. View at Publisher · View at Google Scholar · View at PubMed
  99. U. Trefzer, G. Weingart, Y. Chen, et al., “Hybrid cell vaccination for cancer immune therapy: first clinical trial with metastatic melanoma,” International Journal of Cancer, vol. 85, no. 5, pp. 618–626, 2000.
  100. T. Kikuchi, Y. Akasaki, T. Abe, et al., “Vaccination of glioma patients with fusions of dendritic and glioma cells and recombinant human interleukin 12,” Journal of Immunotherapy, vol. 27, no. 6, pp. 452–459, 2004.
  101. T. Kikuchi, Y. Akasaki, M. Irie, S. Homma, T. Abe, and T. Ohno, “Results of a phase I clinical trial of vaccination of glioma patients with fusions of dendritic and glioma cells,” Cancer Immunology, Immunotherapy, vol. 50, no. 7, pp. 337–344, 2001. View at Publisher · View at Google Scholar
  102. J. Fu, D. Xu, Z. Liu, et al., “Increased regulatory T cells correlate with CD8 T-cell impairment and poor survival in hepatocellular carcinoma patients,” Gastroenterology, vol. 132, no. 7, pp. 2328–2339, 2007. View at Publisher · View at Google Scholar · View at PubMed
  103. M. A. Morse, A. C. Hobeika, T. Osada, et al., “Depletion of human regulatory T cells specifically enhances antigen-specific immune responses to cancer vaccines,” Blood, vol. 112, no. 3, pp. 610–618, 2008.
  104. B. Vasir, Z. Wu, K. Crawford, et al., “Fusions of dendritic cells with breast carcinoma stimulate the expansion of regulatory T cells while concomitant exposure to IL-12, CpG oligodeoxynucleotides, and anti-CD3/CD28 promotes the expansion of activated tumor reactive cells,” The Journal of Immunology, vol. 181, no. 1, pp. 808–821, 2008.
  105. S. Homma, Y. Sagawa, M. Ito, T. Ohno, and G. Toda, “Cancer immunotherapy using dendritic/tumour-fusion vaccine induces elevation of serum anti-nuclear antibody with better clinical responses,” Clinical and Experimental Immunology, vol. 144, no. 1, pp. 41–47, 2006. View at Publisher · View at Google Scholar · View at PubMed
  106. R. Savai, R. T. Schermuly, S. S. Pullamsetti, et al., “A combination hybrid-based vaccination/adoptive cellular therapy to prevent tumor growth by involvement of T cells,” Cancer Research, vol. 67, no. 11, pp. 5443–5453, 2007. View at Publisher · View at Google Scholar · View at PubMed