Differential antitumor effect of interleukin-12 family cytokines on orthotopic hepatocellular carcinoma.
BACKGROUND
Hepatocellular carcinoma (HCC) is one of the most difficult cancers to treat. The interleukin (IL)-12 family cytokines, including IL-12, IL-23 and IL-27, display overlapping, but not redundant, roles in regulating lymphocyte subpopulations. IL-12 is known as a potent antitumor cytokine, whereas the results of the antitumor effect of IL-23 and IL-27 are inconsistent. The present study aimed to directly compare the relative antitumor efficacy of these three IL-12 family cytokines on HCC.


METHODS
A murine orthotopic BNL HCC model, in which the tumor is located in an environment heavily populated with different lymphocyte subsets, was established. The hepatotropic adeno-associated virus serotype 8 (AAV8) vector was used to deliver the cytokine genes aiming to achieve sustained cytokine expression in the liver.


RESULTS
AAV8/IL-12 treatment significantly reduced hepatic metastases and prolonged survival time, whereas treatment with AAV8/IL-23 or AAV8/IL-27 had only moderate antitumor effects at a high dose. The antitumor efficacy of these cytokines was positively correlated with their ability to regulate hepatic T cells, natural killer cells and natural killer T cells, with IL-12 greatly increasing the number and activation status of these cells, whereas IL-27 had no effect and IL-23 had a negative effect. AAV8/IL-12 treatment also resulted in a marked decrease in tumor vessel density, which was not observed with AAV8/IL-23 and AAV8/IL-27 treatment.


CONCLUSIONS
The data obtained in the present study highlight the importance of local lymphocytes and anti-angiogenesis for influencing the antitumor activity of these three IL-12 family cytokines and suggest that IL-12 is the best candidate for treating HCC.
Lo
Chia-Hui
CH
Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan.
Chang
Chia-Ming
CM
Tang
Shih-Wen
SW
Pan
Wen-Yu
WY
Fang
Cheng-Chieh
CC
Chen
Yin
Y
Wu
Ping-Yi
PY
Chen
Kai-Yun
KY
Ma
Hsin-I
HI
Xiao
Xiao
X
Tao
Mi-Hua
MH
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002452:Cell Count; D000229:Dependovirus / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D005822:Genetic Vectors / Q000235:genetics; D007150:Immunohistochemistry; D018664:Interleukin-12 / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use*; D020381:Interleukin-17 / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D053759:Interleukin-23 / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000188:drug therapy
D000970:Antineoplastic Agents; D020381:Interleukin-17; D053759:Interleukin-23; D018664:Interleukin-12