High efficacy of a Listeria-based vaccine against metastatic breast cancer reveals a dual mode of action.
High efficacy of a Listeria-based vaccine against metastatic breast cancer reveals a dual mode of action.
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DOI：
10.1158/0008-5472.can-08-4855
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发表时间：
2009-07-15
期刊：
影响因子：
11.2
通讯作者：
Gravekamp C
中科院分区：
文献类型：
--
作者：
Kim SH;Castro F;Paterson Y;Gravekamp C
大多数肿瘤疫苗诱导细胞毒性T淋巴细胞(CTL)对肿瘤相关抗原(TAA)的反应。对肿瘤细胞的杀伤是通过TAA特异性CTL介导的细胞溶解来实现的。在这里，我们展示了在同基因侵袭性小鼠乳腺肿瘤模型4T1中，一次预防和两次基于减毒单核细胞增多性李斯特氏菌(Listeria monuctoto，LM)疫苗的治疗性免疫可以根除所有转移和几乎整个原发肿瘤。我们提供了强有力的证据表明，这是李斯特菌感染肿瘤细胞的直接杀伤和针对李斯特菌抗原的CTL反应共同作用的结果。电子显微镜观察证实，表达截短型溶血素O(LLO)和TAA MAGE-b的311-660氨基酸片段的LM(LM-LLO-MAGE-B311-660)和对照菌株LM-LLO在体内外均能感染肿瘤细胞。体外实验数据表明，肿瘤细胞的死亡是通过激活烟酰胺腺嘌呤二核苷酸磷酸酶(NADPH)氧化酶和增加细胞内钙离子水平而发生的，两者都导致了高ROS水平的产生。由于LM-LLO和LM-LLO-MAGE-B311-660在体内表现出同样强的药效，因此我们得出结论：LM-LLO是关键的，MAGE-b次之。我们在小鼠的脾中发现了对LM-LLO的强烈的CTL反应，体内CD8 T细胞的耗尽导致了显著的肿瘤再生长(52%)，这表明LM-LLO特异性的CTL确实在体内对肿瘤细胞的杀伤起到了部分作用。基于李斯特菌的疫苗的这种双重作用模式以前从未被描述过，可能会为开发更有效的抗转移性乳腺癌疫苗提供新的方向。
Most cancer vaccines induce cytotoxic T lymphocyte (CTL) responses to tumor-associated antigens (TAA). Killing of tumor cells occurs through TAA-specific CTL-mediated cytolysis. Here we show that one preventive followed by two therapeutic immunizations with an attenuated Listeria monocytogenes (LM)-based vaccine eradicates all metastases and almost the entire primary tumor in the syngeneic, aggressive mouse breast tumor model 4T1. We provide strong evidence that this is due to the combined result of direct kill by Listeria infecting the tumors cells, and by CTL responses against Listeria antigens. We demonstrated by electron microscopy (EM) that LM expressing truncated lysteriolysinO (LLO) and amino acid fragment 311-660 of TAA Mage-b (LM-LLO-Mage-b311-660) and the control strain LM-LLO infect tumor cells in vitro and in vivo. In vitro data indicate that tumor cell death occurs through activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and increased intracellular Ca2+ levels, both resulting in the production of high ROS levels. Since both LM-LLO and LM-LLO-Mage-b311-660 showed equally strong efficacies in vivo we concluded that LM-LLO was crucial and Mage-b of less importance. We found strong CTL responses to LM-LLO in the spleen, and depletion of CD8 T cells in vivo resulted in significant tumor re-growth (52%) in LM-LLO-vaccinated mice, indicating that LM-LLO-specific CTL indeed partially contributed to tumor cell kill in vivo. This dual mode of action of a Listeria-based vaccine has not been described before and may provide new directions in the development of more effective vaccines against metastatic breast cancer.