IL-15 is a component of the inflammatory milieu in the tumor microenvironment promoting antitumor responses
IL-15 is a component of the inflammatory milieu in the tumor microenvironment promoting antitumor responses
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DOI：
10.1073/pnas.1814642116
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发表时间：
2019-01-08
影响因子：
11.1
通讯作者：
Schluns, Kimberly S.
中科院分区：
文献类型：
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作者：
Carrero, Rosa M. Santana;Beceren-Braun, Figen;Schluns, Kimberly S.
先前的研究已经提供证据表明，人类肿瘤中IL-15的表达对于最佳的抗肿瘤反应至关重要；然而，IL-15在肿瘤微环境（TME）中的调控尚不清楚。我们在此报道，在植入各种肿瘤细胞系的小鼠的分析中，可溶性IL-15/IL-15R α复合物（sIL-15复合物）在肿瘤间质液中丰富，并且在肿瘤浸润淋巴细胞浸润之前表达。此外，IL-15以及调节IL-15的I型IFN是在肿瘤中建立正常数量的CD8 T细胞和自然杀伤细胞所必需的。根据不同的肿瘤类型，肿瘤和基质都是sIL-15复合物的来源。在对IL-15报告小鼠的分析中，TME中大多数髓系细胞表达IL-15，其中CD11b(+)Ly6C（hi）细胞表达量最多，表明IL-15蛋白在肿瘤中有很大的来源，它被隔离在肿瘤基质内。尽管il -15表达细胞丰富，但sIL-15复合物的相对水平在晚期肿瘤中较低，但可以通过局部刺激因子干扰素基因（STING）激活而上调。此外，虽然使用STING激动剂治疗肿瘤会导致肿瘤消退，但最佳的STING介导的免疫和远处继发性肿瘤的消退需要IL-15的表达。总之，我们的研究揭示了IL-15在TME中的动态调控及其在抗肿瘤免疫中的重要性。这些发现提供了对肿瘤景观的一个未被认识的属性的见解，该属性有助于抗肿瘤免疫，这可以通过治疗来控制以增强抗肿瘤反应。
Previous studies have provided evidence that IL-15 expression within human tumors is crucial for optimal antitumor responses; however, the regulation of IL-15 within the tumor microenvironment (TME) is unclear. We report herein, in analyses of mice implanted with various tumor cell lines, soluble IL-15/IL-15R alpha complexes (sIL-15 complexes) are abundant in the interstitial fluid of tumors with expression preceding the infiltration of tumor-infiltrating lymphocytes. Moreover, IL-15 as well as type I IFN, which regulates IL-15, was required for establishing normal numbers of CD8 T cells and natural killer cells in tumors. Depending on tumor type, both the tumor and the stroma are sources of sIL-15 complexes. In analyses of IL-15 reporter mice, most myeloid cells in the TME express IL-15 with CD11b(+)Ly6C(hi) cells being the most abundant, indicating there is a large source of IL-15 protein in tumors that lies sequestered within the tumor stroma. Despite the abundance of IL-15-expressing cells, the relative levels of sIL-15 complexes are low in advanced tumors but can be up-regulated by local stimulator of IFN genes (STING) activation. Furthermore, while treatment of tumors with STING agonists leads to tumor regression, optimal STING-mediated immunity and regression of distant secondary tumors required IL-15 expression. Overall, our study reveals the dynamic regulation of IL-15 in the TME and its importance in antitumor immunity. These findings provide insight into an unappreciated attribute of the tumor landscape that contributes to antitumor immunity, which can be manipulated therapeutically to enhance antitumor responses.