Strengthening of antitumor immune memory and prevention of thymic atrophy mediated by adenovirus expressing IL-12 and GM-CSF
Strengthening of antitumor immune memory and prevention of thymic atrophy mediated by adenovirus expressing IL-12 and GM-CSF
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DOI：
10.1038/gt.2011.125
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发表时间：
2012-07-01
期刊：
影响因子：
5.1
通讯作者：
Yun, C-O
中科院分区：
文献类型：
--
作者：
Choi, K-J;Zhang, S-N;Yun, C-O
白细胞介素（IL）-12和粒细胞-单核细胞集落刺激因子（GM-CSF）最近已被用作肿瘤基因治疗的免疫抑制剂。IL-12和GM-CSF在抗肿瘤免疫应答中具有不同的作用，因为IL-12靶向T、NK和自然杀伤T（NKT）细胞，而GM-CSF主要靶向抗原呈递细胞（APC）。为了增强这两种细胞因子的治疗效果，我们产生了共表达IL-12和GM-CSF的溶瘤腺病毒（Ad），Ad-Delta B7/IL-12/GM-CSF。使用鼠B16-F10同基因肿瘤模型，我们表明，与单独表达IL-12或GM-CSF的溶瘤Ad（分别为Ad-Delta B7/IL 12或Ad-Delta B7/GMCSF）相比，Ad-Delta B7/IL 12/GMCSF促进抗肿瘤应答并增加存活。通过测量细胞毒性T淋巴细胞活性和干扰素-γ的产生，我们表明，增强的治疗效果介导的诱导免疫细胞的细胞毒性。Ad-DeltaB 7/IL 12/GMCSF的原位递送导致CD 4（+）T细胞、CD 8（+）T细胞、NK细胞和CD 86（+）APC大量浸润到肿瘤坏死区周围的组织中。此外，GM-CSF有效地促进抗肿瘤免疫记忆，IL-12显著增强了这种免疫记忆。最后，表达IL 12的溶瘤腺病毒可预防肿瘤诱导的胸腺萎缩，并与胸腺细胞凋亡减少和增殖增加有关。总之，这些数据表明，共表达IL-12和GM-CSF的溶瘤Ad是治疗癌症的潜在治疗工具。Gene Therapy（2012）19，711-723; doi：10.1038/gt.2011.125; 2011年10月13日在线发表
Interleukin (IL)-12 and granulocyte-monocyte colony-stimulating factor (GM-CSF) have recently been used as immunotherapeutic agents in cancer gene therapy. IL-12 and GM-CSF have differential roles in the antitumor immune response, as IL-12 targets T, NK and natural killer T (NKT) cells and GM-CSF principally targets antigen-presenting cells (APCs). To strengthen the therapeutic efficacy of these two cytokines, we generated an oncolytic adenovirus (Ad), Ad-Delta B7/IL12/GMCSF, coexpressing IL-12 and GM-CSF. Using a murine B16-F10 syngeneic tumor model, we show that Ad-Delta B7/IL12/GMCSF promoted antitumor responses and increased survival compared with an oncolytic Ad expressing IL-12 or GM-CSF alone (Ad-Delta B7/IL12 or Ad-Delta B7/GMCSF, respectively). By measuring cytotoxic T lymphocyte activity and interferon-gamma production, we show that the enhanced therapeutic effect was mediated by the induction of immune cell cytotoxicity. In situ delivery of Ad-Delta B7/IL12/GMCSF resulted in massive infiltration of CD4(+) T cells, CD8(+) T cells, NK cells and CD86(+) APCs into the tissue surrounding the necrotic area of the tumor. Moreover, GM-CSF effectively promoted antitumor immune memory, which was significantly augmented by IL-12. Lastly, IL12-expressing oncolytic Ads prevented tumor-induced thymic atrophy and was associated with reduced apoptosis and increased proliferation in the thymus. Taken together, these data demonstrate that an oncolytic Ad coexpressing IL-12 and GM-CSF is a potential therapeutic tool for the treatment of cancer. Gene Therapy (2012) 19, 711-723; doi:10.1038/gt.2011.125; published online 13 October 2011