Synergistic antitumor effect by coexpression of chemokine CCL21 SLC and costimulatory molecule LIGHT

• Published in: Cancer gene therapy Vol. 11; no. 4; pp. 280 - 288
• Main Authors: Hisada, Masayuki, Yoshimoto, Takayuki, Kamiya, Sadahiro, Magami, Yasushi, Miyaji, Hiroko, Yoneto, Toshihiko, Tamada, Koji, Aoki, Tatuya, Koyanagi, Yasuhisa, Mizuguchi, Junichiro
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.04.2004
• Subjects: Animals; Antitumor activity; Cancer; Carcinoma - therapy; Care and treatment; CCL21 protein; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell Line, Tumor; Chemokine CCL21; Chemokines; Chemokines, CC - genetics; Chemokines, CC - metabolism; Chemotaxis, Leukocyte; Colonic Neoplasms - therapy; Cytotoxicity; Dendritic cells; Dendritic Cells - immunology; Female; Gene Expression - genetics; Genetic aspects; Health aspects; Humans; Immunotherapy; Infiltration; Interferon-gamma - biosynthesis; Lymphocytes; Lymphocytes T; Lymphoid tissue; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metastases; Methods; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms, Experimental - immunology; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - therapy; Physiological aspects; Remission; RNA, Messenger - analysis; Solid tumors; Spleen; Survival Rate; Transfection; Tumor Necrosis Factor Ligand Superfamily Member 14; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; γ-Interferon; Japan
• ISSN: 0929-1903; 1476-5500
• DOI: 10.1038/sj.cgt.7700676

To establish a more efficient treatment for immunotherapy against solid tumors, we have evaluated the antitumor effect by coexpression of a chemokine CCL21/secondary lymphoid tissue chemokine and a costimulatory molecule LIGHT in colon carcinoma C26. C26 cells expressing either CCL21 or LIGHT exhibited a significantly reduced tumor growth in vivo, and mice inoculated with these cells showed a prolonged survival, but eventually all these mice died. In contrast, C26 cells expressing both CCL21 and LIGHT exhibited a minimal tumor growth in vivo, and all these mice survived healthily with a tumor remission and consequently acquired a strong protective immunity. A markedly increased infiltration of mature dendritic cells (DCs), and CD8(+) T cells was observed in the tumor mass, and their spleen cells showed a greatly enhanced cytotoxic T lymphocyte (CTL) activity against C26 tumor and interferon (IFN)-gamma production. Neutralization of IFN-gamma or depletion of CD8(+) or CD4(+) T cells significantly reduced the antitumor activity. These results suggest that the combined treatment with CCL21 and LIGHT is able to induce a synergistic antitumor effect to eradicate tumor completely by greatly enhancing tumor-infiltration of lymphocytes including mature DCs and CD8(+) T cells, resulting in markedly augmented CTL activity and IFN-gamma production.