Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid induces an effective CD8+ T-cell-mediated antitumor immune response in murine models of lung cancer and mesothelioma
Activation of tumor-associated macrophages by the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid induces an effective CD8+ T-cell-mediated antitumor immune response in murine models of lung cancer and mesothelioma
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DOI：
10.1158/0008-5472.can-05-1658
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发表时间：
2005-12-15
期刊：
影响因子：
11.2
通讯作者：
Albelda, SM
中科院分区：
文献类型：
--
作者：
Jassar, AS;Suzuki, E;Albelda, SM
5,6-二甲基氧杂蒽酮-4-乙酸 (DMXAA) 是黄酮类中的一种小分子，其具有抗肿瘤活性，被认为是由于能够诱导局部高水平的肿瘤坏死因子 (TNF)-α，从而破坏肿瘤内已建立的血管。该药物已完成人体 I 期试验，目前正在进行与化疗联合使用的 2 期试验。尽管被描述为“血管破坏剂”；一些研究表明 DMXAA 也会对免疫系统产生影响，这对其功效很重要。本研究的目的是仔细确定 DMXAA 在一系列具有不同免疫学特征的小鼠肺癌和间皮瘤细胞系中的免疫作用。我们发现，DMXAA 有效激活肿瘤相关巨噬细胞，释放多种免疫刺激细胞因子和趋化因子，包括 TNF-α； IFN-诱导蛋白-10；白细胞介素-6;巨噬细胞炎症蛋白-2；单核细胞趋化蛋白-1；并调节激活、正常 T 细胞的表达和分泌。 DMXAA 治疗对于小型和大型胁腹肿瘤均非常有效。通过 DMXAA 治愈肿瘤的动物会产生全身记忆反应，并对肿瘤细胞的再次攻击产生抵抗力。 DMXAA 治疗导致巨噬细胞初始肿瘤浸润，随后 CD8(+) T 细胞涌入。这些CD8+T细胞是抗肿瘤功效所必需的，因为裸鼠、CD8+T细胞耗尽的小鼠和穿孔素敲除小鼠中肿瘤抑制活性丧失，但CD4+T细胞耗尽的小鼠则不会丧失。这些数据表明，DMXAA 激活肿瘤相关巨噬细胞是产生 CD8(+) T 细胞依赖性抗肿瘤免疫反应的有效方法，即使在具有相对非免疫原性肿瘤的动物中也是如此。鉴于这些特性，DMXAA 也可能可用于支持其他形式的免疫疗法。
5,6-Dimethylxanthenone-4-acetic acid (DMXAA) is a small molecule in the flavanoid class that has antitumor activity thought to be due to ability to induce high local levels of tumor necrosis factor (TNF)-alpha that disrupt established blood vessels within tumors. The drug has completed phase I testing in humans and is currently in phase 2 trials in combination with chemotherapy. Although characterized as a "vascular disrupting agent;" there are some studies suggesting that DMXAA also has effects on the immune system that are important for its efficacy. The goal of this study was to carefully define the immune effects of DMXAA in a series of murine lung cancer and mesothelioma cell lines with varying immunologic characteristics. We show that DMXAA efficiently activated tumor-associated macrophages to release a variety of immunostimulatory cytokines and chemokines, including TNF-alpha; IFN-inducible protein-10; interleukin-6; macrophage inflammatory protein-2; monocyte chemotactic protein-1; and regulated on activation, normal T-cell expressed, and secreted. DMXAA treatment was highly effective in both small and large flank tumors. Animals cured of tumors by DMXAA generated a systemic memory response and were resistant to tumor cell rechallenge. DMXAA treatment led to initial tumor infiltration with macrophages that was followed by an influx of CD8(+) T cells. These CD8(+) T cells were required for antitumor efficacy because tumor inhibitory activity was lost in nude mice, mice depleted of CD8(+) T cells, and perforin knockout mice, but not in CD4(+) T-cell-depleted mice. These data show that activation of tumor-associated macrophages by DMXAA is an efficient way to generate a CD8(+) T-cell-dependent antitumor immune response even in animals with relatively nonimmunogenic tumors. Given these properties, DMXAA might also be useful in hoosting other forms of immunotherapy.