Injection of IL-12 gene-transduced dendritic cells into mouse liver tumor lesions activates both innate and acquired immunity.
Dendritic cell (DC)-based vaccines have been applied clinically in the setting of advanced-stage cancer. To date, the clinical efficacy of these vaccines has been limited, possibly owing to the impairment of transferred DC function in cancer-bearing patients. In this study, we examined the therapeutic efficacy of interleukin-12 (IL-12) gene-transfected DCs isolated from tumor-bearing hosts against liver tumor. The endogenous DCs isolated from subcutaneous (s.c.) CMS4 tumor-bearing mice (CMS4DC) exhibited decreased expression levels of antigen-presenting molecules and low-allostimulatory capacity. CMS4DC produced less IL-12p70 than DCs isolated from normal mice. Adenoviral transfection of IL-12 gene into CMS4DC (AdIL12DC) restored the expression of antigen-presenting molecules and allostimulatory capacity. Intratumoral (i.t.) delivery of AdIL12DC resulted in complete rejection of intrahepatic CMS4 tumors and activation of innate and acquired immune cells. Antibody depletion studies revealed that both CD4(+) and CD8(+) T cells as well as natural killer cells play critical roles in mediating liver tumor rejection. I.t. treatment of AdIL12DC resulted in long-term protection against s.c. rechallenge with CMS4 tumor cells. These results revealed that IL-12 gene transfer is capable of improving the impaired functions of DC isolated from tumor-bearing hosts, and support the preclinical therapeutic efficacy of intrahepatic injection of AdIL12DC.
Tatsumi
T
T
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
Takehara
T
T
Yamaguchi
S
S
Sasakawa
A
A
Miyagi
T
T
Jinushi
M
M
Sakamori
R
R
Kohga
K
K
Uemura
A
A
Ohkawa
K
K
Storkus
W J
WJ
Hayashi
N
N
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D016219:Immunotherapy, Adoptive / Q000379:methods*; D015552:Injections, Intralesional; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology; D008113:Liver Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000628:therapy*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D013997:Time Factors; D014161:Transduction, Genetic / Q000379:methods
D019496:Cancer Vaccines; D018664:Interleukin-12