T-cell-dependent antitumor effects produced by CD40 ligand expressed on mouse lung carcinoma cells are linked with the maturation of dendritic cells and secretion of a variety of cytokines.
CD40/CD40 ligand (CD40L) interaction plays an essential role in cell-mediated immune responses. We examined whether expression of CD40L in murine lung carcinoma (A11) cells could produce antitumor effects. The proliferation rate in vitro of A11 cells transfected with the murine CD40L gene (A11/CD40L) was not different from that of parent cells; however, half of the immunocompetent mice inoculated with A11/CD40L cells did not form tumors and the growth of A11/CD40L tumors developed in the rest of mice was significantly retarded compared with that of parent tumors. Protective immunity was also induced in the mice that had rejected A11/CD40L cells. In T-cell-defective nude mice, these antitumor effects were not observed. Bone-marrow-derived dendritic cells (DCs), when cultured with A11/CD40L cells, formed clusters with the tumors and showed upregulated CD86 expression. Expression of the interleukin-23 (IL-23) p19, IL-12p35, IL-18, interferon-gamma (IFN-gamma) and Mig (monokine induced by IFN-gamma) genes was induced in the DCs that were cultured with A11/CD40L but not with A11 cells, and P40, the subunit of both IL-12 and IL-23, was secreted from the cocultured DCs. These data directly showed that the expression of CD40L in tumors facilitated the interaction between DCs and the tumors, enhanced the maturation of DCs, induced secretion of cytokines, and consequently produced T-cell-dependent systemic immunity.
Tada
Yuji
Y
Division of Pathology, Chiba Cancer Center Research Institute, 666-2 Nitona, Chuo-ku, Chiba 260-8717, Japan.
O-Wang
Jiyang
J
Yu
Ling
L
Shimozato
Osamu
O
Wang
Yan-Qing
YQ
Takiguchi
Yuichi
Y
Tatsumi
Koichiro
K
Kuriyama
Takayuki
T
Takenaga
Keizo
K
Sakiyama
Shigeru
S
Tagawa
Masatoshi
M
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D051940:B7-2 Antigen; D023201:CD40 Ligand / Q000378:metabolism*; D018827:Carcinoma, Lewis Lung; D002455:Cell Division; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000096:biosynthesis; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D016133:Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
D015703:Antigens, CD; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D016207:Cytokines; C508841:Il23a protein, mouse; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma