Enhancement of cancer vaccine therapy by systemic delivery of a tumor-targeting Salmonella-based STAT3 shRNA suppresses the growth of established melanoma tumors.
Enhancement of cancer vaccine therapy by systemic delivery of a tumor-targeting Salmonella-based STAT3 shRNA suppresses the growth of established melanoma tumors.
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DOI：
10.1158/0008-5472.can-10-4676
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发表时间：
2011-06-15
期刊：
影响因子：
11.2
通讯作者：
Diamond DJ
中科院分区：
文献类型：
--
作者：
Manuel ER;Blache CA;Paquette R;Kaltcheva TI;Ishizaki H;Ellenhorn JD;Hensel M;Metelitsa L;Diamond DJ
癌症疫苗疗法在专注于效应免疫时仅取得了有限的成功，其目标是引发强大的肿瘤特异性T细胞应答。最近，人们逐渐认识到，只有通过协调破坏肿瘤源性免疫抑制才能实现有效的免疫。为了实现这一目标，我们开发了一种有效的基于沙门氏菌的疫苗，表达密码子优化的生存素（CO-SVN），称为3342 Max。当单独用作治疗性疫苗时，3342 Max可减弱过表达SVN的侵袭性鼠黑素瘤的生长。然而，在更多的免疫抑制条件下，例如与较大肿瘤体积相关的条件下，我们发现疫苗无效。如果最初用编码靶向致耐受性分子STAT 3的shRNA（YS 1646-shSTAT 3）的沙门氏菌治疗荷瘤小鼠，则可以挽救疫苗效力。在接种疫苗的小鼠中，沉默STAT 3增加了肿瘤内CD 4+和CD 8 + T细胞的增殖和颗粒酶B水平。联合策略还增加了治疗小鼠肿瘤中的细胞凋亡，增强了对肿瘤靶点的肿瘤特异性杀伤。有趣的是，单独用YS 1646-shSTAT 3或3342 Max治疗的小鼠在排斥已建立的肿瘤方面同样不成功，而组合方案是高度有效的。我们的研究结果表明，沉默免疫抑制分子然后接种疫苗的组合策略可以协同作用以减弱肿瘤生长，并且它们为改善肿瘤免疫治疗提供了一种新的翻译方向。
Cancer vaccine therapies have only achieved limited success when focusing on effector immunity with the goal of eliciting robust tumor-specific T cell responses. More recently, there is an emerging understanding that effective immunity can only be achieved by coordinate disruption of tumor-derived immune suppression. Towards that goal, we have developed a potent Salmonella-based vaccine expressing codon-optimized survivin (CO-SVN) referred to as 3342Max. When used alone as a therapeutic vaccine, 3342Max can attenuate growth of aggressive murine melanomas overexpressing SVN. However, under more immunosuppressive conditions, such as those associated with larger tumor volumes, we found that the vaccine was ineffective. Vaccine efficacy could be rescued if tumor-bearing mice were treated initially with Salmonella encoding a shRNA targeting the tolerogenic molecule STAT3 (YS1646-shSTAT3). In vaccinated mice, silencing STAT3 increased the proliferation and granzyme B levels of intratumoral CD4+ and CD8+ T cells. The combined strategy also increased apoptosis in tumors of treated mice, enhancing tumor-specific killing of tumor targets. Interestingly, mice treated with YS1646-shSTAT3 or 3342Max alone were similarly unsuccessful in rejecting established tumors, while the combined regimen was highly potent. Our findings establish that a combined strategy of silencing immunosuppressive molecules followed by vaccination can act synergistically to attenuate tumor growth, and they offer a novel translational direction to improve tumor immunotherapy.