Synergistic antitumor effect by coexpression of chemokine CCL21/SLC and costimulatory molecule LIGHT.
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.
Intractable Immune System Disease Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
Masayuki
M
Hisada
Takayuki
T
Yoshimoto
Sadahiro
S
Kamiya
Yasushi
Y
Magami
Hiroko
H
Miyaji
Toshihiko
T
Yoneto
Koji
K
Tamada
Tatuya
T
Aoki
Yasuhisa
Y
Koyanagi
Junichiro
J
Mizuguchi
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002277:Carcinoma / Q000628:therapy; D045744:Cell Line, Tumor; D054421:Chemokine CCL21; D019742:Chemokines, CC / Q000235:genetics* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D003110:Colonic Neoplasms / Q000628:therapy; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D012333:RNA, Messenger / Q000032:analysis; D015996:Survival Rate; D014162:Transfection; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
C515478:CCL21 protein, human; C515479:Ccl21c protein, mouse; D054421:Chemokine CCL21; D019742:Chemokines, CC; D008565:Membrane Proteins; D012333:RNA, Messenger; C505914:TNFSF14 protein, human; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma