α-Tocopheryloxyacetic acid: a novel chemotherapeutic that stimulates the antitumor immune response.
α-Tocopheryloxyacetic acid: a novel chemotherapeutic that stimulates the antitumor immune response.
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DOI：
10.1186/bcr2808
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发表时间：
2011-01-13
期刊：
影响因子：
--
通讯作者：
Akporiaye ET
中科院分区：
文献类型：
--
作者：
Hahn T;Jagadish B;Mash EA;Garrison K;Akporiaye ET
α-生育酚氧乙酸(α-TEA)是一种新型的α-生育酚的乙醚衍生物，由于其对肿瘤细胞的选择性毒性以及在各种啮齿动物和人类异种移植模型中抑制肿瘤生长的能力而引起人们对化疗药物的兴趣。我们之前报道过口服α-TEA抑制移植(4T1)和自发性乳腺癌模型小鼠的生长。由于对体内α-TEA效应可能的免疫学机制知之甚少，我们通过表征肿瘤部位的免疫细胞群来评估α-TEA治疗对免疫反应的影响。α-TEA治疗后，肿瘤微环境中活化的T细胞的比例增加，CD_4~+和CD_8~+T细胞与调节性T细胞的比率分别提高2倍和6倍。这一发现与α-TEA处理的小鼠的肿瘤引流淋巴细胞和脾细胞分泌干扰素-γ的能力增强有关，它们分别以肿瘤特异性的方式分泌干扰素-CD3或介导细胞溶解反应。当α+和CD8+T细胞被耗尽时，部分肿瘤抑制被证明了CD4TEA介导的抗肿瘤作用具有T细胞依赖成分。我们还检测了肿瘤内细胞因子和趋化因子的分布，发现α-TEA治疗增加了肿瘤内干扰素-γ的水平，但降低了白细胞介素4的水平，提示肿瘤向Th1反应转变。此外，α-TEA可诱导更高水平的炎性细胞因子IL-6和趋化因子CCL5。综上所述，这些数据表明，α-TEA治疗，除了其直接的细胞毒作用外，还增强了抗肿瘤免疫反应。这项研究有助于更好地了解α-TEA的作用机制及其对免疫系统的影响，并可能被证明有助于设计免疫刺激策略，以增强α-TEA对乳腺癌患者的抗肿瘤作用。
α-Tocopheryloxyacetic acid (α-TEA) is a novel ether derivative of α-tocopherol that has generated interest as a chemotherapeutic agent because of its selective toxicity toward tumor cells and its ability to suppress tumor growth in various rodent and human xenograft models. We previously reported that oral α-TEA inhibited the growth of both a transplanted (4T1) and a spontaneous MMTV-PyMT mouse model of breast cancer. Because little is known about the possible immunological mechanisms underlying the in vivo α-TEA effects, we evaluated the impact of α-TEA therapy on the immune response by characterizing immune cell populations infiltrating the tumor site. α-TEA treatment resulted in higher frequencies of activated T cells in the tumor microenvironment and twofold and sixfold higher ratios of CD4+ and CD8+ T cells to regulatory T cells, respectively. This finding was correlated with an increased ability of tumor-draining lymph node cells and splenocytes from α-TEA-treated mice to secrete interferon (IFN)-γ in response to CD3 or to mediate a cytolytic response in a tumor-specific fashion, respectively. That the α-TEA-mediated antitumor effect had a T cell-dependent component was demonstrated by the partial abrogation of tumor suppression when CD4+ and CD8+ T cells were depleted. We also determined the intratumoral cytokine and chemokine profile and found that α-TEA treatment increased intratumoral IFN-γ levels but decreased interleukin (IL)-4 levels, suggesting a shift toward a TH1 response. In addition, α-TEA induced higher levels of the inflammatory cytokine IL-6 and the chemokine CCL5. Taken together, these data suggest that α-TEA treatment, in addition to its direct cytotoxic effects, enhanced the anti-tumor immune response. This study provides a better understanding of the mechanisms of action of α-TEA and its effect on the immune system and may prove useful in designing immune-stimulating strategies to boost the antitumor effects of α-TEA in breast cancer patients.
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发表时间：
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期刊：
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影响因子：
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作者：
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