Ahn Woong-Shick, Bae Su-Mi, Kim Tae-Yoon, Kim Tai-Gyu, Lee Joon-Mo, Namkoong Sung Eun, Kim Chong Kook, Sin Jeong-Im
Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, 137-040, Korea.
Hum Gene Ther. 2003 Oct 10;14(15):1389-99. doi: 10.1089/104303403769211619.
Interleukin (IL)-12 has been reported to induce cellular immune responses for protection against tumor formation. Here we investigate the utility of adenoviral delivery of IL-12 as an adjuvant for a human papillomavirus E7 subunit vaccine in a mouse tumor challenge model. Direct intratumoral injection of AdIL-12 resulted in a significant suppression of tumor growth compared to the control group. Injection of E7 protein into either a tumor site or the distance site along with AdIL-12 further enhanced antitumor effects significantly higher than either AdIL-12 or E7 injection alone. This combined injection resulted in complete regression of 9-mm-sized tumor in 40% of animals as well as lasting antitumor immunity against tumor recurrence. We also evaluated immune responses induced by these injections. AdIL-12 plus E7 enhanced E7-specific antibody responses significantly higher than AdIL-12 or E7 injection. In particular, the production level of interferon (IFN)-gamma from E7-specific CD4(+) T cells was similar between AdIL-12 group and AdIL-12 + E7 group. However, IFN-gamma production from E7-specific CD8(+) T cells was the most significant when injected with AdIL-12 + E7. This was consistent with intracellular IFN-gamma staining levels of CD8(+) T cells, suggesting that AdIL-12 + E7 injection enhances antitumor immunity in the human papillomavirus (HPV) 16 tumor model through increased expansion of the cytotoxic T-lymphocyte (CTL) subset. This enhanced protection appeared to be mediated by CD8(+) T cells, as determined by in vivo T-cell subset deletion. Thus, these studies demonstrate that E7 vaccines can induce CTL responses responsible for antitumor effects in the presence of IL-12 delivered via adenovirus vectors. This likely provides one additional approach for immune therapy against cervical cancers.
据报道，白细胞介素（IL）-12可诱导细胞免疫反应以预防肿瘤形成。在此，我们在小鼠肿瘤攻击模型中研究腺病毒递送IL-12作为人乳头瘤病毒E7亚单位疫苗佐剂的效用。与对照组相比，直接瘤内注射AdIL-12可显著抑制肿瘤生长。将E7蛋白注射到肿瘤部位或远处部位并同时注射AdIL-12，其抗肿瘤效果进一步显著增强，明显高于单独注射AdIL-12或E7。这种联合注射使40%的动物体内9毫米大小的肿瘤完全消退，并产生针对肿瘤复发的持久抗肿瘤免疫力。我们还评估了这些注射诱导的免疫反应。AdIL-12加E7增强E7特异性抗体反应的程度显著高于注射AdIL-12或E7。特别是，AdIL-12组和AdIL-12 + E7组中E7特异性CD4(+) T细胞产生干扰素（IFN）-γ的水平相似。然而，注射AdIL-12 + E7时，E7特异性CD8(+) T细胞产生的IFN-γ最为显著。这与CD8(+) T细胞的细胞内IFN-γ染色水平一致，表明AdIL-12 + E7注射通过增加细胞毒性T淋巴细胞（CTL）亚群的扩增来增强人乳头瘤病毒（HPV）16肿瘤模型中的抗肿瘤免疫力。如体内T细胞亚群缺失所确定的，这种增强的保护作用似乎由CD8(+) T细胞介导。因此，这些研究表明，在通过腺病毒载体递送IL-12的情况下，E7疫苗可诱导产生负责抗肿瘤作用的CTL反应。这可能为宫颈癌的免疫治疗提供了另一种方法。
