IL-12 immunotherapy of Braf(V600E)-induced papillary thyroid cancer in a mouse model.

Abstract

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.

• Authors: Ranjit S Parhar, Minjing Zou, Futwan A Al-Mohanna, Essa Y Baitei, Abdullah M Assiri, Brian F Meyer, Yufei Shi
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 96 Issue 1 Pg. 89-97 (Jan 2016) ISSN: 1530-0307 [Electronic] United States
• PMID: 26501867 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Transforming Growth Factor beta
• Interleukin-12
• Proto-Oncogene Proteins B-raf

Topics

• Animals
• Carcinoma (mortality, therapy)
• Carcinoma, Papillary
• Disease Models, Animal
• Immunotherapy (methods)
• Interleukin-12 (administration & dosage, therapeutic use)
• Macrophages (metabolism)
• Mice
• Mice, Transgenic
• Mutation
• Proto-Oncogene Proteins B-raf (genetics, metabolism)
• Thyroid Cancer, Papillary
• Thyroid Neoplasms (mortality, therapy)
• Transforming Growth Factor beta (metabolism)