Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Bone Marrow Transplantation Laboratory, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
Cancer Immunol Res. 2017 Dec;5(12):1098-1108. doi: 10.1158/2326-6066.CIR-17-0341. Epub 2017 Oct 25.
Several host factors may affect the spread of cancer to distant organs; however, the intrinsic role of dendritic cells (DC) in controlling metastasis is poorly described. Here, we show in several tumor models that although the growth of primary tumors in Batf3-deficient mice, which lack cross-presenting DCs, was not different from primary tumors in wild-type (WT) control mice, Batf3-deficient mice had increased experimental and spontaneous metastasis and poorer survival. The increased metastasis was independent of CD4 and CD8 T lymphocytes, but required NK cells and IFNγ. Chimeric mice in which Batf3-dependent DCs uniformly lacked the capacity to produce IL12 had metastatic burdens similar to the Batf3-deficient mice, suggesting that Batf3 DCs were the only cell type whose IL12 production was critical for controlling metastasis. We found that IL12-YFP reporter mice, whose lungs were injected with B16F10 melanoma, had increased numbers of IL12-expressing CD103 DCs with enhanced CD86 expression. Bone-marrow-derived DCs from WT, but not Batf3-deficient, mice activated NK cells to produce IFNγ in an IL12-dependent manner and therapeutic injection of recombinant mouse IL12 decreased metastasis in both WT and Batf3-deficient mice. Analysis of TCGA datasets revealed an association between high expression of and and improved survival of breast cancer patients; expression also significantly correlated with NK-cell receptor genes, , and Collectively, our findings show that IL12 from CD103 DCs is critical for NK cell-mediated control of tumor metastasis. .
几种宿主因素可能影响癌症向远处器官的扩散；然而，树突状细胞 (DC) 在控制转移中的内在作用描述得很差。在这里，我们在几种肿瘤模型中表明，尽管缺乏交叉呈递 DC 的 Batf3 缺陷型小鼠原发性肿瘤的生长与野生型 (WT) 对照小鼠的原发性肿瘤没有不同，但 Batf3 缺陷型小鼠的实验和自发转移增加，生存率降低。这种转移的增加与 CD4 和 CD8 T 淋巴细胞无关，但需要 NK 细胞和 IFNγ。Batf3 依赖性 DC 均缺乏产生 IL12 能力的嵌合小鼠具有与 Batf3 缺陷型小鼠相似的转移负担，这表明 Batf3 DC 是唯一一种其 IL12 产生对控制转移至关重要的细胞类型。我们发现，用 B16F10 黑色素瘤注射肺部的 IL12-YFP 报告小鼠具有更多数量的表达增强的 CD86 的表达 IL12 的 CD103 DC。WT 但不是 Batf3 缺陷型骨髓来源的 DC 以 IL12 依赖的方式激活 NK 细胞产生 IFNγ，而重组鼠 IL12 的治疗性注射可降低 WT 和 Batf3 缺陷型小鼠的转移。TCGA 数据集的分析表明， 和 的高表达与乳腺癌患者的生存改善有关； 表达还与 NK 细胞受体基因 、 和 显著相关。综上所述，我们的研究结果表明，CD103 DC 产生的 IL12 对于 NK 细胞介导的肿瘤转移控制至关重要。
