Kim Juyang, Kim Wonyoung, Moon U J, Kim Hyun J, Choi Hye-Jeong, Sin Jeong-Im, Park Neung H, Cho Hong R, Kwon Byungsuk
Biomedical Research Center, Ulsan University Hospital and School of Medicine, University of Ulsan, Ulsan 682-714, Republic of Korea;
School of Biological Sciences, University of Ulsan, Ulsan 680-749, Republic of Korea;
J Immunol. 2016 Mar 1;196(5):2410-23. doi: 10.4049/jimmunol.1501730. Epub 2016 Feb 1.
A long-standing question in the field of tumor immunotherapy is how Th2 cytokines block tumor growth. Their antitumor effects are particularly prominent when they are secreted continuously in tumors, suggesting that Th2 cytokines may create a tumor microenvironment unfavorable for tumor growth independently of adaptive immunity. In this study, we show that local production of IL-33 establishes a high number of type 2 innate lymphoid cells (ILC2s) with potent antitumor activity. IL-33 promotes secretion of a massive amount of CXCR2 ligands from ILC2s but creates a tumor microenvironment where tumor cells express CXCR2 through a dysfunctional angiogenesis/hypoxia/reactive oxygen species axis. These two signaling events converge to reinforce tumor cell-specific apoptosis through CXCR2. Our results identify a previously unrecognized antitumor therapeutic pathway wherein ILC2s play a central role.
肿瘤免疫治疗领域长期存在的一个问题是Th2细胞因子如何阻断肿瘤生长。当它们在肿瘤中持续分泌时，其抗肿瘤作用尤为突出，这表明Th2细胞因子可能独立于适应性免疫而创造一个不利于肿瘤生长的肿瘤微环境。在本研究中，我们发现局部产生的IL-33可建立大量具有强大抗肿瘤活性的2型固有淋巴细胞（ILC2s）。IL-33促进ILC2s分泌大量CXCR2配体，但会创造一个肿瘤微环境，其中肿瘤细胞通过功能失调的血管生成/缺氧/活性氧轴表达CXCR2。这两个信号事件通过CXCR2共同作用，加强肿瘤细胞特异性凋亡。我们的结果确定了一条以前未被认识的抗肿瘤治疗途径，其中ILC2s发挥核心作用。
