IL-12 immunotherapy of Braf(V600E)-induced papillary thyroid cancer in a mouse model.
Papillary thyroid carcinoma (PTC) accounts for >80% thyroid malignancies, and BRAF(V600E) mutation is frequently found in >40% PTC. Interleukin-12 (IL-12) is a proinflammatory heterodimeric cytokine with strong antitumor activity. It is not known whether IL-12 immunotherapy is effective against Braf(V600E)-induced PTC. In the present study, we investigated the effectiveness of IL-12 immunotherapy against Braf(V600E)-induced PTC in LSL-Braf(V600E)/TPO-Cre mice. LSL-Braf(V600E)/TPO-Cre mice were created for thyroid-specific expression of Braf(V600E) under the endogenous Braf promoter, and spontaneous PTC developed at about 5 weeks of age. The mice were subjected to two treatment regimens: (1) weekly intramuscular injection of 50 μg plasmid DNA expressing a single-chain IL-12 fusion protein (scIL-12/CMVpDNA), (2) daily intraperitoneal injection of mouse recombinant IL-12 protein (mrIL-12, 100 ng per day). The role of T cells, natural killer (NK) cells, and transforming growth factor-β (TGF-β) in IL-12-mediated antitumor effects was determined by a (51)Cr-release cytotoxicity assay. Tumor size and weight were significantly reduced by either weekly intramuscular injection of scIL-12/CMVpDNA or daily intraperitoneal injection of mrIL-12, and tumor became more localized. Survival was significantly increased when treatment started at 1 week of age as compared with that at the 6 weeks of age. Both NK and CD8(+) T cells were involved in the cytotoxicity against tumor cells and their antitumor activity was significantly reduced in tumor-bearing mice. TGF-β also inhibited the antitumor activity of NK and CD8(+) T cells. The immune suppression was completely reversed by IL-12 treatment and partially recovered by anti-TGF-β antibody. We conclude that both IL-12 gene therapy and recombinant protein therapy are effective against PTC. Given that the immune response is significantly suppressed in tumor-bearing mice and can be restored by IL-12, the current study raises a possibility of the application of IL-12 as an adjuvant therapy for thyroid cancer.
Department of Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Ranjit S
RS
Parhar
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Minjing
M
Zou
Department of Cell Biology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Futwan A
FA
Al-Mohanna
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Essa Y
EY
Baitei
Department of Comparative Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Abdullah M
AM
Assiri
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Brian F
BF
Meyer
Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Yufei
Y
Shi
D000818:Animals; D002277:Carcinoma / Q000401:mortality / Q000628:therapy*; D002291:Carcinoma, Papillary; D004195:Disease Models, Animal; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000008:administration & dosage / Q000627:therapeutic use*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000401:mortality / Q000628:therapy*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016212:Transforming Growth Factor beta; D018664:Interleukin-12; D048493:Proto-Oncogene Proteins B-raf