A Listeria-derived polypeptide promotes in vivo activation of NK cells for antitumor therapy.
A Listeria-derived polypeptide promotes in vivo activation of NK cells for antitumor therapy.
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DOI：
10.4049/immunohorizons.1700013
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发表时间：
2017-06-01
期刊：
影响因子：
--
通讯作者：
Lenz LL
中科院分区：
文献类型：
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作者：
Ortiz AL;Lenz LL
免疫疗法在治疗癌症方面已显示出前景，但需要更有效和更有针对性的疗法。自然杀伤（NK）细胞是具有识别和裂解肿瘤细胞的先天能力的淋巴细胞。当被激活时，它们还产生II型干扰素（IFNγ）来协调其他免疫细胞的活动。体内诱导NK细胞活化的策略在抗肿瘤免疫治疗中具有潜在的用途。在这里，我们报告了一种策略，以刺激NK细胞活化和抗肿瘤活性的小鼠与建立B16.F10小鼠黑色素瘤。我们和其他人先前观察到，NK细胞在被病原体如单核细胞增生李斯特菌（Lm）感染期间迅速激活。分泌的Lm毒力蛋白p60和称为L1S的p60片段先前显示刺激先天免疫应答并促进NK细胞活化。我们纯化了重组L1S，并在细胞培养研究中表征其活性。还观察到重组L1S蛋白在通过气管内滴注给予对照和荷瘤小鼠时促进肺中的积累和稳健的NK细胞活化。重要的是，发现单次L1S剂量的治疗性给药显著减少了已建立的B16.F10鼠黑色素瘤小鼠肺上“转移性”肿瘤结节的数量和面积。耗竭研究表明，这些抗肿瘤作用依赖于NK细胞和IFNγ。这些数据提供了概念证明，即施用单一免疫调节微生物多肽可用于治疗性地增强NK细胞体内活化并促进抗肿瘤应答。
Immunotherapies have shown promise in treatment of cancer, but more potent and targeted therapies are needed. Natural killer (NK) cells are lymphocytes with innate ability to recognize and lyse tumor cells. When activated, they also produce type II interferon (IFNγ) to orchestrate the activity of other immune cells. Strategies to elicit NK cell activation in vivo have potential usefulness in anti-tumor immunotherapies. Here, we report on a strategy to stimulate NK cell activation and anti-tumor activity in mice with established B16.F10 murine melanomas. We and others previously observed that NK cells are rapidly activated during infection by pathogens such as the bacterium Listeria monocytogenes (Lm). A secreted Lm virulence protein, p60, and a fragment of p60 termed L1S were previously shown to stimulate innate immune responses and promote NK cell activation. We purified recombinant L1S and characterized its activity in cell culture studies. Recombinant L1S protein was also observed to promote accumulation and robust NK cell activation in the lungs when given via intratracheal instillation to control and tumor-bearing mice. Importantly, therapeutic administration of a single L1S dose was found to significantly reduce the number and area of “metastatic” tumor nodules on the lungs of mice with established B16.F10 murine melanomas. Depletion studies showed that these antitumor effects were dependent on NK cells and IFNγ. These data provide proof of concept that administration of a single immune-modulating microbial polypeptide can be used to therapeutically boost NK cell in vivo activation and promote anti-tumor responses.