Oncolytic adenovirus coexpressing interleukin-12 and decorin overcomes Treg-mediated immunosuppression inducing potent antitumor effects in a weakly immunogenic tumor model.
Oncolytic adenovirus coexpressing interleukin-12 and decorin overcomes Treg-mediated immunosuppression inducing potent antitumor effects in a weakly immunogenic tumor model.
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DOI：
10.18632/oncotarget.13972
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发表时间：
2017-01-17
期刊：
影响因子：
--
通讯作者：
Yun CO
中科院分区：
文献类型：
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作者：
Oh E;Choi IK;Hong J;Yun CO
白细胞介素（IL）-12是一种有效的抗肿瘤细胞因子。然而，含有转化生长因子-β（TGF-β）的免疫抑制性肿瘤微环境减弱了姜黄素介导的抗肿瘤免疫应答。为了增强IL-12介导的癌症免疫疗法的功效，探索核心蛋白聚糖（DCN）作为克服TGF-β介导的免疫抑制的佐剂。我们设计并构建了一种共表达IL-12和DCN的溶瘤腺病毒（RdB/IL-12/DCN）。与用表达单一治疗基因的同源对照溶瘤Ad（RdB/DCN或RdB/IL 12）处理的肿瘤相比，RdB/IL 12/DCN处理的肿瘤显示出显著更高水平的干扰素（IFN）-γ、肿瘤坏死因子-α、单核细胞趋化蛋白-1和分泌IFN-γ的免疫细胞。此外，RdB/IL 12/DCN减弱了肿瘤内TGF-β的表达，这与引流淋巴结和肿瘤组织中Treg细胞的减少呈正相关。此外，用RdB/IL 12/DCN处理的肿瘤组织显示出CD 8 + T细胞浸润的增加和肿瘤组织内的病毒扩散。这些结果表明，在弱免疫原性鼠4 T1原位乳腺癌模型中，共表达IL-12和DCN的溶瘤Ad通过恢复抗肿瘤免疫功能诱导有效的抗肿瘤免疫应答。这些发现为IL-12加DCN的治疗机制提供了新的见解，使其成为克服肿瘤诱导的免疫抑制的有前途的癌症免疫抑制剂。
Interleukin (IL)-12 is a potent antitumor cytokine. However, immunosuppressive tumor microenvironments containing transforming growth factor-β (TGF-β) attenuate cytokine-mediated antitumor immune responses. To enhance the efficacy of IL-12-mediated cancer immunotherapy, decorin (DCN) was explored as an adjuvant for overcoming TGF-β-mediated immunosuppression. We designed and generated a novel oncolytic adenovirus (Ad) coexpressing IL-12 and DCN (RdB/IL12/DCN). RdB/IL12/DCN-treated tumors showed significantly greater levels of interferon (IFN)-γ, tumor necrosis factor-α, monocyte chemoattractant protein-1, and IFN-γ-secreting immune cells than tumors treated with cognate control oncolytic Ad expressing a single therapeutic gene (RdB/DCN or RdB/IL12). Moreover, RdB/IL12/DCN attenuated intratumoral TGF-β expression, which positively correlated with reduction of Treg cells in draining lymph nodes and tumor tissues. Furthermore, tumor tissue treated with RdB/IL12/DCN showed increases infiltration of CD8+ T cells and proficient viral spreading within tumor tissues. These results demonstrated that an oncolytic Ad co-expressing IL-12 and DCN induces a potent antitumor immune response via restoration of antitumor immune function in a weakly immunogenic murine 4T1 orthotopic breast cancer model. These findings provide new insights into the therapeutic mechanisms of IL-12 plus DCN, making it a promising cancer immunotherapeutic agent for overcoming tumor-induced immunosuppression.