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Antitumor effects of the MIG and IP-10 genes transferred with poly [D,L-2,4-diaminobutyric acid] on murine neuroblastoma

Abstract

The number of tumor-infiltrating lymphocytes is known to be related to outcomes in patients with a variety of malignancies. Interferon (IFN) γ-inducible protein-10 (IP-10) and monokine induced by IFNγ (MIG) have chemotactic effects on activated T lymphocytes and natural killer (NK) cells. The aim of this study was to evaluate the antitumor effects of exogenous expression of the MIG and IP-10 genes delivered to solid tumors by poly [D,L-2,4-diaminobutyric acid] (PDBA). The murine MIG and IP-10 genes were transfected into mouse neuroblastoma cells with PDBA. MIG and IP-10 levels in supernatants of transfected cells were measured by enzyme-linked immunosorbent assay. The chemotactic activities of MIG and IP-10 in the supernatants of cell cultures were measured by chemotaxis assay. Tumors were injected in vivo with PDBA/pmMIGIP-10 complexes to evaluate the effects of these genes on tumor volume and survival time of mice. Transfected PDBA/pmMIGIP-10 complexes produced MIG and IP-10 protein in vitro. MIG and IP-10 proteins secreted into the culture medium showed chemotactic activity. MIG and IP-10 gene therapy with the PDBA system in vivo significantly inhibited tumor growth and prolonged survival time of mice. In conclusion, PDBA-mediated MIG and IP-10 gene therapy may be useful for treatment of solid tumors.

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References

  1. Ono SJ, Nakamura T, Miyazaki D, Ohbayashi M, Dawson M, Toda M . Chemokines: roles in leukocyte development, trafficking, and effector function. J Allergy Clin Immunol 2003; 111: 1185–1199.

    Article  CAS  PubMed  Google Scholar 

  2. Guo J, Wang B, Zhang M, Chen T, Yu Y, Regulier E et al. Macrophage-derived chemokine gene transfer results in tumor regression in murine lung carcinoma model through efficient induction of antitumor immunity. Gene Ther 2002; 9: 793–803.

    Article  CAS  PubMed  Google Scholar 

  3. Schroers R, Sinha I, Segall H, Schmidt-Wolf IG, Rooney CM, Brenner MK et al. Transduction of human PBMC-derived dendritic cells and macrophages by an HIV-1-based lentiviral vector system. Mol Ther 2000; 1: 171–179.

    Article  CAS  PubMed  Google Scholar 

  4. Xia DJ, Zhang WP, Zheng S, Wang J, Pan JP, Wang Q et al. Lymphotactin cotransfection enhances the therapeutic efficacy of dendritic cells genetically modified with melanoma antigen gp100. Gene Ther 2002; 9: 592–601.

    Article  CAS  PubMed  Google Scholar 

  5. Yoong KF, Afford SC, Jones R, Aujla P, Qin S, Price K et al. Expression and function of CXC and CC chemokines in human malignant liver tumors: a role for human monokine induced by gamma-interferon in lymphocyte recruitment to hepatocellular carcinoma. Hepatology 1999; 30: 100–111.

    Article  CAS  PubMed  Google Scholar 

  6. Liao F, Rabin RL, Yannelli JR, Koniaris LG, Vanguri P, Farber JM . Human Mig chemokine: biochemical and functional characterization. J Exp Med 1995; 182: 1301–1314.

    Article  CAS  PubMed  Google Scholar 

  7. Jinquan T, Jing C, Jacobi HH, Reimert CM, Millner A, Quan S et al. CXCR3 expression and activation of eosinophils: role of IFN-gamma-inducible protein-10 and monokine induced by IFN-gamma. J Immunol 2000; 165: 1548–1556.

    Article  CAS  PubMed  Google Scholar 

  8. Rabin RL, Park MK, Liao F, Swofford R, Stephany D, Farber JM . Chemokine receptor responses on T cells are achieved through regulation of both receptor expression and signaling. J Immunol 1992; 162: 3840–3850.

    Google Scholar 

  9. Amichay D, Gazzinelli RT, Karupiah G, Moench TR, Sher A, Farber JM . Genes for chemokines MuMig and Crg-2 are induced in protozoan and viral infections in response to IFN-gamma with patterns of tissue expression that suggest nonredundant roles in vivo. J Immunol 1996; 157: 4511–4520.

    CAS  PubMed  Google Scholar 

  10. Maghazachi AA, Skalhegg BS, Rolstad B, Al-Aoukaty A . Interferon-inducible protein-10 and lymphotactin induce the chemotaxis and mobilization of intracellular calcium in natural killer cells through pertussis toxin-sensitive and -insensitive heterotrimeric G-proteins. FASEB J 1997; 11: 765–774.

    Article  CAS  PubMed  Google Scholar 

  11. Taub DD, Lloyd AR, Conlon K, Wang JM, Ortaldo JR, Harada A et al. Recombinant human interferon-inducible protein 10 is a chemoattractant for human monocytes and T lymphocytes and promotes T cell adhesion to endothelial cells. J Exp Med 1993; 177: 1809–1814.

    Article  CAS  PubMed  Google Scholar 

  12. Bramson JL, Hitt M, Addison CL, Muller WJ, Gauldie J, Graham FL . Direct intratumoral injection of an adenovirus expressing interleukin-12 induces regression and long-lasting immunity that is associated with highly localized expression of interleukin-12. Hum Gene Ther 1996; 7: 1995–2002.

    Article  CAS  PubMed  Google Scholar 

  13. Caruso M, Pham-Nguyen K, Kwong YL, Xu B, Kosai KI, Finegold M et al. Adenovirus-mediated interleukin-12 gene therapy for metastatic colon carcinoma. Proc Natl Acad Sci USA 1996; 93: 11302–11306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Tahara H, Zitvogel L, Storkus WJ, Zeh III HJ, McKinney TG, Schreiber RD et al. Effective eradication of established murine tumors with IL-12 gene therapy using a polycistronic retroviral vector. J Immunol 1995; 154: 6466–6474.

    CAS  PubMed  Google Scholar 

  15. Iwashita Y, Ogawa T, Goto S, Nakanishi M, Goto T, Kitano S . Effective transfer of interleukin-12 gene to solid tumors using a novel gene delivery system, poly [D,L-2,4-diaminobutyric acid]. Cancer Gene Ther 2004; 11: 103–108.

    Article  CAS  PubMed  Google Scholar 

  16. Jass JR . Lymphocytic infiltration and survival in rectal cancer. J Clin Pathol 1986; 39: 585–589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Svennevig JL, Lunde OC, Holter J, Bjorgsvik D . Lymphoid infiltration and prognosis in colorectal carcinoma. Br J Cancer 1984; 49: 375–377.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Aaltomaa S, Lipponen P, Eskelinen M, Kosma VM, Marin S, Alhava E et al. Lymphocyte infiltrates as a prognostic variable in female breast cancer. Eur J Cancer 1992; 28A: 859–864.

    Article  CAS  PubMed  Google Scholar 

  19. Furukawa T, Watanabe S, Kodama T, Sato Y, Shimosato Y, Suemasu K . T-zone histiocytes in adenocarcinoma of the lung in relation to postoperative prognosis. Cancer 1985; 56: 2651–2656.

    Article  CAS  PubMed  Google Scholar 

  20. Tsujitani S, Furukawa T, Tamada R, Okamura T, Yasumoto K, Sugimachi K . Langerhans cells and prognosis in patients with gastric carcinoma. Cancer 1987; 59: 501–505.

    Article  CAS  PubMed  Google Scholar 

  21. Clark Jr WH, Elder DE, Guerry Dt, Braitman LE, Trock B, Schultz D et al. Model predicting survival in stage I melanoma based on tumor progression. J Natl Cancer Inst 1989; 81: 1893–1904.

    Article  PubMed  Google Scholar 

  22. Clemente CG, Mihm Jr MC, Bufalino R, Zurrida S, Collini P, Cascinelli N . Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer 1996; 77: 1303–1310.

    Article  CAS  PubMed  Google Scholar 

  23. Hirano S, Iwashita Y, Sasaki A, Kai S, Ohta M, Kitano S . Increased mRNA expression of chemokines in hepatocellular carcinoma with tumor-infiltrating lymphocytes. J Gastroenterol Hepatol 2007; 22: 690–696.

    CAS  PubMed  Google Scholar 

  24. Fossum B, Gedde-Dahl III T, Breivik J, Eriksen JA, Spurkland A, Thorsby E et al. p21-ras-peptide-specific T-cell responses in a patient with colorectal cancer. CD4+ and CD8+ T cells recognize a peptide corresponding to a common mutation (13Gly → Asp). Int J Cancer 1994; 56: 40–45.

    Article  CAS  PubMed  Google Scholar 

  25. Meta M, Ponte M, Guastella M, Semino C, Pietra G, Ratto GB et al. Detection of oligoclonal T lymphocytes in lymph nodes draining from advanced non-small-cell lung cancer. Cancer Immunol Immunother 1995; 40: 235–240.

    Article  CAS  PubMed  Google Scholar 

  26. Naito H, Ziegler MM, Miyakawa A, Tokunaga O, Sasaki M . Establishment of animal liver metastatic model for C-1300 murine neuroblastoma and immunotherapy for it using OK-432, streptococcus preparation. J Surg Res 1992; 52: 79–84.

    Article  CAS  PubMed  Google Scholar 

  27. Keyser J, Schultz J, Ladell K, Elzaouk L, Heinzerling L, Pavlovic J et al. IP-10-encoding plasmid DNA therapy exhibits anti-tumor and anti-metastatic efficiency. Exp Dermatol 2004; 13: 380–390.

    Article  CAS  PubMed  Google Scholar 

  28. Plotz SG, Traidl-Hoffmann C, Feussner I, Kasche A, Feser A, Ring J et al. Chemotaxis and activation of human peripheral blood eosinophils induced by pollen-associated lipid mediators. J Allergy Clin Immunol 2004; 113: 1152–1160.

    Article  CAS  PubMed  Google Scholar 

  29. Haas AR, Sun J, Vachani A, Wallace AF, Silverberg M, Kapoor V et al. Cycloxygenase-2 inhibition augments the efficacy of a cancer vaccine. Clin Cancer Res 2006; 12: 214–222.

    Article  CAS  PubMed  Google Scholar 

  30. Zlotnik A, Yoshie O . Chemokines: a new classification system and their role in immunity. Immunity 2000; 12: 121–127.

    Article  CAS  PubMed  Google Scholar 

  31. Yoshie O, Imai T, Nomiyama H . Chemokines in immunity. Adv Immunol 2001; 78: 57–110.

    Article  CAS  PubMed  Google Scholar 

  32. Homey B, Muller A, Zlotnik A . Chemokines: agents for the immunotherapy of cancer? Nat Rev Immunol 2002; 2: 175–184.

    Article  CAS  PubMed  Google Scholar 

  33. Paillard F . Cytokine and chemokine: a stimulating couple. Hum Gene Ther 1999; 10: 695–696.

    Article  CAS  PubMed  Google Scholar 

  34. Sharma S, Stolina M, Luo J, Strieter RM, Burdick M, Zhu LX et al. Secondary lymphoid tissue chemokine mediates T cell-dependent antitumor responses in vivo. J Immunol 2000; 164: 4558–4563.

    Article  CAS  PubMed  Google Scholar 

  35. Miyata T, Yamamoto S, Sakamoto K, Morishita R, Kaneda Y . Novel immunotherapy for peritoneal dissemination of murine colon cancer with macrophage inflammatory protein-1beta mediated by a tumor-specific vector, HVJ cationic liposomes. Cancer Gene Ther 2001; 8: 852–860.

    Article  CAS  PubMed  Google Scholar 

  36. Guo J, Zhang M, Wang B, Yuan Z, Guo Z, Chen T et al. Fractalkine transgene induces T-cell-dependent antitumor immunity through chemoattraction and activation of dendritic cells. Int J Cancer 2003; 103: 212–220.

    Article  CAS  PubMed  Google Scholar 

  37. Loetscher M, Gerber B, Loetscher P, Jones SA, Piali L, Clark-Lewis I et al. Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes. J Exp Med 1996; 184: 963–969.

    Article  CAS  PubMed  Google Scholar 

  38. Sgadari C, Angiolillo AL, Cherney BW, Pike SE, Farber JM, Koniaris LG et al. Interferon-inducible protein-10 identified as a mediator of tumor necrosis in vivo. Proc Natl Acad Sci USA 1996; 93: 13791–13796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sgadari C, Farber JM, Angiolillo AL, Liao F, Teruya-Feldstein J, Burd PR et al. Mig, the monokine induced by interferon-gamma, promotes tumor necrosis in vivo. Blood 1997; 89: 2635–2643.

    CAS  PubMed  Google Scholar 

  40. Kanegane C, Sgadari C, Kanegane H, Teruya-Feldstein J, Yao L, Gupta G et al. Contribution of the CXC chemokines IP-10 and Mig to the antitumor effects of IL-12. J Leukoc Biol 1998; 64: 384–392.

    Article  CAS  PubMed  Google Scholar 

  41. Huang H, Liu Y, Xiang J . Synergistic effect of adoptive T-cell therapy and intratumoral interferon gamma-inducible protein-10 transgene expression in treatment of established tumors. Cell Immunol 2002; 217: 12–22.

    Article  CAS  PubMed  Google Scholar 

  42. Narvaiza I, Mazzolini G, Barajas M, Duarte M, Zaratiegui M, Qian C et al. Intratumoral coinjection of two adenoviruses, one encoding the chemokine IFN-gamma-inducible protein-10 and another encoding IL-12, results in marked antitumoral synergy. J Immunol 2000; 164: 3112–3122.

    Article  CAS  PubMed  Google Scholar 

  43. Huang H, Xiang J . Synergistic effect of lymphotactin and interferon gamma-inducible protein-10 transgene expression in T-cell localization and adoptive T-cell therapy of tumors. Int J Cancer 2004; 109: 817–825.

    Article  CAS  PubMed  Google Scholar 

  44. Young LS, Searle PF, Onion D, Mautner V . Viral gene therapy strategies: from basic science to clinical application. J Pathol 2006; 208: 299–318.

    Article  CAS  PubMed  Google Scholar 

  45. Wells DJ . Gene therapy progress and prospects: electroporation and other physical methods. Gene Ther 2004; 11: 1363–1369.

    Article  CAS  PubMed  Google Scholar 

  46. Micka B, Trojaneck B, Niemitz S, Lefterova P, Kruopis S, Huhn D et al. Comparison of non-viral transfection methods in melanoma cell primary cultures. Cytokine 2000; 12: 828–833.

    Article  CAS  PubMed  Google Scholar 

  47. Iwashita Y, Tahara K, Goto S, Sasaki A, Kai S, Seike M et al. A phase I study of autologous dendritic cell-based immunotherapy for patients with unresectable primary liver cancer. Cancer Immunol Immunother 2003; 52: 155–161.

    CAS  PubMed  Google Scholar 

  48. Sadanaga N, Nagashima H, Mashino K, Tahara K, Yamaguchi H, Ohta M et al. Dendritic cell vaccination with MAGE peptide is a novel therapeutic approach for gastrointestinal carcinomas. Clin Cancer Res 2001; 7: 2277–2284.

    CAS  PubMed  Google Scholar 

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Correspondence to M Tominaga.

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Tominaga, M., Iwashita, Y., Ohta, M. et al. Antitumor effects of the MIG and IP-10 genes transferred with poly [D,L-2,4-diaminobutyric acid] on murine neuroblastoma. Cancer Gene Ther 14, 696–705 (2007). https://doi.org/10.1038/sj.cgt.7701059

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