Abstract
Interleukin-12 (IL-12) is a promising candidate for cancer immunotherapy because of its ability to activate a number of host immune subsets that recognize and destroy cancer cells. We found that human hepatocellular carcinoma (HCC) patients with higher than median levels of IL-12 have significantly favorable clinical outcomes. Here, we report that a messenger RNA (mRNA) lipid nanoparticle delivering IL-12 (IL-12-LNP) slows down the progression of MYC oncogene-driven HCC. IL-12-LNP was well distributed within the HCC tumor and was not associated with significant animal toxicity. Treatment with IL-12-LNP significantly reduced liver tumor burden measured by dynamic magnetic resonance imaging (MRI), and increased survival of MYC-induced HCC transgenic mice in comparison to control mice. Importantly, IL-12-LNP exhibited no effect on transgenic MYC levels confirming that its therapeutic efficacy was not related to the downregulation of a driver oncogene. IL-12-LNP elicited marked infiltration of activated CD44+ CD3+ CD4+ T helper cells into the tumor, and increased the production of Interferon γ (IFNγ). Collectively, our findings suggest that IL-12-LNP administration may be an effective immunotherapy against HCC.
Highlights
Cytokines are crucial signaling mediators that alert the immune system to the presence of foreign antigens
We examined if the expression of IL-12 messenger RNA (mRNA) in the surrounding normal liver tissue of human hepatocellular carcinoma (HCC) patients can predict clinical outcome
We evaluated the efficacy of a novel IL-12 mRNA therapy in our primary tetracycline-inducible transgenic mouse model of v-myc avian myelocytomatosis viral oncogene homolog (MYC) oncogene-driven HCC [25] (Fig. 1b)
Summary
Cytokines are crucial signaling mediators that alert the immune system to the presence of foreign antigens. Cytokine treatment may be an effective immune therapy for the treatment of cancer. Interleukin-12 (IL-12) has anti-tumor activity in a variety of preclinical models [1,2,3,4,5,6]. The anti-tumor activity of IL-12 can be attributed to its ability to bridge innate and adaptive immune surveillance mechanisms, thereby creating a long-lasting immune response against cancers [7]. Administration of IL-12 has been previously demonstrated to have therapeutic benefits in multiple preclinical models of cancer, such as breast [16], liver [17, 18], and colon [19]. The lack of intravenous approaches to robustly deliver IL-12 to the tumor and avoid cytotoxicity of the surrounding normal tissues has
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