BATF3-dependent genes control tumor rejection induced by dendritic cells independently of cross-presentation
BATF3-dependent genes control tumor rejection induced by dendritic cells independently of cross-presentation
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BATF3依赖性基因控制树突状细胞诱导的肿瘤排斥，与交叉呈递无关
DOI：
10.1158/2326-6066.cir-18-0138
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发表时间：
2018
影响因子：
10.1
通讯作者：
Murphy Theresa L
中科院分区：
文献类型：
--
作者：
Theisen Derek J;Ferris Stephen T;Brise?o Carlos G;Kretzer Nicole;Iwata Arifumi;Murphy Kenneth M.;Murphy Theresa L
常规树突状细胞（cDC）的BATF 3依赖性cDC 1谱系是免疫原性肉瘤排斥和检查点阻断治疗期间进行性肉瘤排斥所必需的。cDC 1谱系的一个独特功能是肿瘤衍生的新抗原向CD 8 +T细胞的有效交叉呈递，但尚不清楚这是否是肿瘤排斥所需的cDC 1的唯一独特功能。我们以前的研究表明，BATF 3在cDC 1谱系定型过程中发挥作用，以维持特定cDC 1祖细胞中IRF 8的表达。然而，由于cDC 1祖细胞在Batf 3 −/−小鼠中不会发育成成熟的cDC 1，因此目前尚不清楚BATF 3是否在成熟的cDC 1细胞中具有额外的功能。转基因Irf 8-Venus报告基因等位基因增加了IRF 8蛋白浓度，足以使Batf 3 −/−小鼠脾脏中的cDC 1自主发育。这些恢复的Batf 3 −/− cDC 1在转录上与对照野生型cDC 1相似，但减少了一组有限的cDC 1特异性基因的表达。恢复的Batf 3 −/− cDC 1能够在体外和体内交叉呈递细胞相关抗原。然而，Batf 3 −/− cDC 1在体内表现出改变的特性，并且不能介导肿瘤排斥。这些结果表明，BATF 3除了调节Irf 8的表达以稳定cDC 1谱系定型外，还控制cDC 1介导的肿瘤排斥所需的一小部分基因的表达。这些BATF 3调节的基因可能是旨在促进肿瘤排斥的免疫治疗中的有用靶点。
The BATF3-dependent cDC1 lineage of conventional dendritic cells (cDC) is required for rejection of immunogenic sarcomas and for rejection of progressive sarcomas during checkpoint blockade therapy. One unique function of the cDC1 lineage is the efficient cross-presentation of tumor-derived neoantigens to CD8+T cells, but it is not clear that this is the only unique function of cDC1 required for tumor rejection. We previously showed that BATF3 functions during cDC1 lineage commitment to maintain IRF8 expression in the specified cDC1 progenitor. However, since cDC1 progenitors do not develop into mature cDC1s inBatf3−/−mice, it is still unclear whether BATF3 has additional functions in mature cDC1 cells. A transgenicIrf8-Venus reporter allele increases IRF8 protein concentration sufficiently to allow autonomous cDC1 development in spleens ofBatf3−/−mice. These restoredBatf3−/−cDC1s are transcriptionally similar to control wild-type cDC1s but have reduced expression of a restricted set of cDC1-specific genes. RestoredBatf3−/−cDC1s are able to cross-present cell-associated antigens bothin vitroandin vivo. However,Batf3−/−cDC1 exhibit altered characteristicsin vivoand are unable to mediate tumor rejection. These results show that BATF3, in addition to regulatingIrf8expression to stabilize cDC1 lineage commitment, also controls expression of a small set of genes required for cDC1-mediated tumor rejection. These BATF3-regulated genes may be useful targets in immunotherapies aimed at promoting tumor rejection.