Macrophage-derived chemokine gene transfer results in tumor regression in murine lung carcinoma model through efficient induction of antitumor immunity.
Chemokine gene transfer represents a promising approach in the treatment of malignancies. Macrophage-derived chemokine (MDC) (CCL22) belongs to the CC chemokine family and is a strong chemoattractant for dendritic cells (DC), NK cells and T cells. Using adenoviral vectors, human MDC gene was transferred in vivo to investigate its efficacy to induce an antitumor response and to determine the immunologic mechanisms involved. We observed that intratumoral injection of recombinant adenovirus encoding human MDC (AdMDC) resulted in marked tumor regression in a murine model with pre-established subcutaneous 3LL lung carcinoma and induced significant CTL activity. The antitumor response was demonstrated to be CD4+ T cell- and CD8+ T cell-dependent. Administration of AdMDC induced chemoattraction of DC to the tumor site, facilitated DC migration to draining lymph nodes or spleen, and finally activated DC to produce high levels of IL-12. Furthermore, a significant increase of IL-4 production within the tumors was observed early after the AdMDC administration and was followed by the increase of IL-12 and IL-2 production. The levels of IL-2, IL-12 and IFN-gamma in serum, lymph nodes and spleen were also found to be higher in mice treated with AdMDC as compared with that in AdLacZ- or PBS-treated mice. The antitumor response induced by AdMDC was markedly impaired in IL-4 knockout mice, suggesting an important role of IL-4 in the induction of antitumor immunity by MDC. These results suggest that MDC gene transfer might elicit significant antitumor effects through efficient induction of antitumor immunity and might be of therapeutic potentials for cancer.
Guo
J
J
Institute of Immunology, Second Military Medical University, Shanghai, PR China.
Wang
B
B
Zhang
M
M
Chen
T
T
Yu
Y
Y
Regulier
E
E
Homann
H E
HE
Qin
Z
Z
Ju
D W
DW
Cao
X
X
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D054422:Chemokine CCL22; D019742:Chemokines, CC / Q000235:genetics*; D003713:Dendritic Cells / Q000276:immunology; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000628:therapy; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014162:Transfection
C515482:CCL22 protein, human; C515483:Ccl22 protein, mouse; D054422:Chemokine CCL22; D019742:Chemokines, CC; D007376:Interleukin-2; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma