Macrophages transduced with an adenoviral vector expressing interleukin 12 suppress tumor growth and metastasis in a preclinical metastatic prostate cancer model.
We investigated the efficacy of intratumoral injection of macrophages transduced with murine IL-12 recombinant adenoviral vector (AdmIL-12) using the orthotopic 178-2 BMA mouse prostate cancer model. AdmIL-12-transduced macrophages secreted IL-12 in vitro and demonstrated increased surface expression of MHC classes I and II as well as F4/80 antigen compared with uninfected macrophages or those infected with an adenoviral vector containing beta-galactosidase (Adbetagal) in control macrophages. AdmIL-12-transduced macrophages injected into orthotopic 178-2 BMA tumors in vivo induced significant suppression of primary tumor growth and spontaneous lung metastases compared with controls. These antitumor and antimetastatic effects were comparable with those resulting from direct orthotopic delivery of the AdmIL-12 vector. Mice with orthotopic tumors treated with AdmIL-12-transduced macrophages survived significantly longer than controls. Analysis of tumors demonstrated significantly increased infiltration of CD4+ and CD8+ T cells in those injected with AdmIL-12-transduced macrophages compared with controls. Splenocyte-derived cytotoxic natural killer cell activity was enhanced on day 2 after AdmIL-12-transduced macrophage injection, and on day 14, tumor-specific T-lymphocyte activities were increased compared with control, Adbetagal-infected macrophages. Trafficking studies confirmed that intratumorally injected, AdmIL-12-transduced macrophages could migrate to draining lymph nodes. Overall, this novel approach to prostate cancer therapy demonstrates antitumor immune responses that provide effective antimetastatic activities in preclinical studies.
Satoh
Takefumi
T
Scott Department of Urology, Baylor College of Medicine, 6560 Fannin, Houston, TX 77030, USA.
Saika
Takashi
T
Ebara
Shin
S
Kusaka
Nobuyuki
N
Timme
Terry L
TL
Yang
Guang
G
Wang
Jianxiang
J
Mouraviev
Vladimir
V
Cao
Guangwen
G
Fattah
El Moataz Abdel
el MA
Thompson
Timothy C
TC
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002455:Cell Division / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism / Q000502:physiology; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic
D018664:Interleukin-12