IL-33 restricts tumor growth and inhibits pulmonary metastasis in melanoma-bearing mice through eosinophils
IL-33 restricts tumor growth and inhibits pulmonary metastasis in melanoma-bearing mice through eosinophils
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DOI：
10.1080/2162402x.2017.1317420
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发表时间：
2017-01-01
期刊：
影响因子：
7.2
通讯作者：
Schiavoni, Giovanna
中科院分区：
文献类型：
--
作者：
Lucarini, Valeria;Ziccheddu, Giovanna;Schiavoni, Giovanna
Alarmin IL-33是IL-1家族成员，其根据靶组织和微环境因素刺激多效性免疫反应。在这项研究中，我们研究了IL-33/ST 2轴在黑色素瘤抗肿瘤反应中的作用。IL-33在小鼠皮下B16.F10黑色素瘤中的注射导致显著的肿瘤生长延迟。这种效应与肿瘤内CD 8（+）T细胞和嗜酸性粒细胞的积聚、免疫抑制性髓样细胞的减少以及局部和全身CD 8（+）T和NK细胞活化的混合Th 1/Th 2细胞因子表达模式相关。此外，鼻内给药IL-33确定了肺中ST 2依赖性嗜酸性粒细胞的募集，从而防止了静脉注射黑色素瘤细胞后肺转移的发生。因此，ST 2缺陷型小鼠发生肺转移的程度高于野生型小鼠，与肺中嗜酸性粒细胞频率较低相关。值得注意的是，通过用抗Siglec-F抗体体内处理消耗嗜酸性粒细胞消除了IL-33限制原发性肿瘤生长和转移形成的能力。最后，我们表明IL-33能够激活嗜酸性粒细胞，从而有效杀死靶黑素瘤细胞，表明IL-33治疗后嗜酸性粒细胞的直接抗肿瘤活性。我们的研究结果主张嗜酸性粒细胞介导的IL-33对黑色素瘤的抗肿瘤功能，从而开辟了新的癌症免疫治疗策略的前景。
The alarmin IL-33 is an IL-1 family member that stimulates pleiotropic immune reactions depending on the target tissue and microenvironmental factors. In this study, we have investigated the role of IL-33/ST2 axis in antitumor response to melanoma. Injection of IL-33 in mice-bearing subcutaneous B16.F10 melanoma resulted in significant tumor growth delay. This effect was associated with intratumoral accumulation of CD8(+) T cells and eosinophils, decrease of immunosuppressive myeloid cells, and a mixed Th1/Th2 cytokine expression pattern with local and systemic activation of CD8(+) T and NK cells. Moreover, intranasal administration of IL-33 determined ST2-dependent eosinophil recruitment in the lung that prevented the onset of pulmonary metastasis after intravenous injection of melanoma cells. Accordingly, ST2-deficient mice developed pulmonary metastasis at higher extent than wild-type counterparts, associated with lower eosinophil frequencies in the lung. Of note, depletion of eosinophils by in vivo treatment with anti-Siglec-F antibody abolished the ability of IL-33 to both restrict primary tumor growth and metastasis formation. Finally, we show that IL-33 is able to activate eosinophils resulting in efficient killing of target melanoma cells, suggesting a direct antitumor activity of eosinophils following IL-33 treatment. Our results advocate for an eosinophil-mediated antitumoral function of IL-33 against melanoma, thus opening perspectives for novel cancer immunotherapy strategies.