Overexpression of IL-15 promotes tumor destruction via NK1.1+ cells in a spontaneous breast cancer model.
Overexpression of IL-15 promotes tumor destruction via NK1.1+ cells in a spontaneous breast cancer model.
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在自发的乳腺癌模型中，IL-15的过表达通过NK1.1+细胞促进肿瘤破坏。
DOI：
10.1186/s12885-015-1264-3
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发表时间：
2015-04-16
期刊：
影响因子：
3.8
通讯作者：
Ashkar AA
中科院分区：
文献类型：
--
作者：
Gillgrass AE;Chew MV;Krneta T;Ashkar AA
自然杀伤(Natural Killer，NK)细胞在肿瘤预防中发挥着重要作用，但一旦肿瘤形成，NK细胞的数量和细胞毒功能就会减少。IL-15是一种增加和激活NK细胞的细胞因子。在这里，我们将研究IL-15在自发性乳腺癌模型中的抗肿瘤作用。为此，将形成自发性乳腺癌的多瘤中T(MT)小鼠与过表达IL-15的小鼠(IL-15转基因(TG))或缺乏IL-15的小鼠(IL-15基因敲除(KO))进行杂交。比较IL-15 KO/MT组、MT组和IL-15 TG/MT组的存活曲线和成瘤情况。通过流式细胞仪、酶联免疫吸附试验、过继转移和抗体清除实验检测NK细胞和CD8T细胞的表型、活化及其在肿瘤形成中的作用。IL-15KO/MT肿瘤的形成和向终点进展较MT肿瘤快。肿瘤细胞凋亡率低，CD8T细胞浸润少。相比之下，IL-15TG/MT组小鼠的存活率明显高于MT组，肿瘤表现为广泛的细胞死亡，活化的NK细胞比例较高，CD8T细胞的浸润率较高。IL-15TG/MT瘤中CD8T细胞具有分泌干扰素γ的能力，具有记忆性，不出现耗竭表型，且多为NK1.1+。在IL-15TG/MT小鼠中的长期抗体耗竭研究表明，NK1.1+而不是CD8T细胞对肿瘤的破坏是关键的。最后，当人类NK细胞暴露在与IL-15TG/MT肿瘤相似的细胞因子环境中时，能够杀死人类乳腺癌细胞。本研究表明，高水平的IL-15可通过对NK1.1+细胞的作用促进肿瘤的破坏，减少乳腺癌的转移。我们的结果表明，旨在提高NK细胞活性的策略可能对实体上皮癌有效。本文的在线版本(doi：10.1186/s12885-0151264-3)包含补充材料，授权用户可以使用。
Natural Killer (NK) cells play an important role in tumor prevention, but once tumors form, the numbers as well as the cytotoxic functions of NK cells are reduced. IL-15 is a cytokine that increases and activates NK cells. Here we will examine the anti-tumor role of IL-15 in a spontaneous breast cancer model. To achieve this, Polyoma Middle T (MT) mice that form spontaneous breast cancer were crossed with mice that either overexpress IL-15 (IL-15 transgenic (TG)) or mice that lack IL-15 (IL-15 knockout (KO)). We compared survival curves and tumor formation in IL-15 KO/MT, MT and IL-15 TG/MT groups. In addition, the phenotype, activation and contribution of NK cells and CD8 T cells to tumor formation were examined in each of these mouse strains via flow cytometry, ELISA, adoptive transfer and antibody depletion experiments. IL-15KO/MT tumors formed and progressed to endpoint more quickly than MT tumors. These tumors displayed little apoptosis and poor CD8 T cell infiltration. In contrast, IL-15 TG/MT mice had increased survival and the tumors displayed extensive cell death, high proportions of activated NK cells and a higher infiltration of CD8 T cells than MT tumors. CD8 T cells in IL-15 TG/MT tumors were capable of secreting IFNγ, possessed markers of memory, did not display an exhausted phenotype and were frequently NK1.1+. Long-term antibody depletion studies in IL-15 TG/MT mice revealed that NK1.1+, but not CD8 T cells, were critical for tumor destruction. Lastly, human NK cells, when exposed to a similar cytokine environment as that found in IL-15TG/MT tumors, were capable of killing human breast cancer cells. This study reveals that high levels of IL-15 can promote tumor destruction and reduce metastasis in breast cancer via effects on NK1.1+ cells. Our results suggest that strategies aimed at increasing NK cell activation may be effective against solid epithelial cancers. The online version of this article (doi:10.1186/s12885-015-1264-3) contains supplementary material, which is available to authorized users.
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DOI：
10.1073/pnas.0503726102
发表时间：
2005-07-05
影响因子：
11.1
作者：
Klebanoff, CA;Gattinoni, L;Restifo, NP
通讯作者：
Restifo, NP
影响因子：
4.4
作者：
Konjevic, Gordana;Jurisic, Vladimir;Spuzic, Ivan
通讯作者：
Spuzic, Ivan
影响因子：
4.4
作者：
Assarsson, E;Kambayashi, T;Chambers, BJ
通讯作者：
Chambers, BJ
影响因子：
5.7
作者：
Bessard, Anne;Sole, Veronique;Jacques, Yannick
通讯作者：
Jacques, Yannick
影响因子：
4.8
作者：
Bruno, Antonino;Focaccetti, Chiara;Noonan, Douglas M.
通讯作者：
Noonan, Douglas M.