Department of Pathology and Immunology, Washington University in St. Louis, School of Medicine, St. Louis, Missouri.
Howard Hughes Medical Institute, Washington University in St. Louis, School of Medicine, St. Louis, Missouri.
Cancer Immunol Res. 2019 Jan;7(1):29-39. doi: 10.1158/2326-6066.CIR-18-0138. Epub 2018 Nov 27.
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 in mice, it is still unclear whether BATF3 has additional functions in mature cDC1 cells. A transgenic -Venus reporter allele increases IRF8 protein concentration sufficiently to allow autonomous cDC1 development in spleens of mice. These restored cDC1s are transcriptionally similar to control wild-type cDC1s but have reduced expression of a restricted set of cDC1-specific genes. Restored cDC1s are able to cross-present cell-associated antigens both and However, cDC1 exhibit altered characteristics and are unable to mediate tumor rejection. These results show that BATF3, in addition to regulating expression 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.
BATF3 依赖性传统树突状细胞 (cDC) 的 cDC1 谱系对于免疫原性肉瘤的排斥和检查点阻断治疗期间进行性肉瘤的排斥是必需的。cDC1 谱系的一个独特功能是有效地将肿瘤来源的新抗原交叉呈递给 CD8 T 细胞，但尚不清楚这是否是 cDC1 排斥肿瘤所必需的唯一独特功能。我们之前表明，BATF3 在 cDC1 谱系的分化过程中发挥作用，以维持指定的 cDC1 祖细胞中 IRF8 的表达。然而，由于 cDC1 祖细胞在 小鼠中不会发育为成熟的 cDC1，因此仍不清楚 BATF3 在成熟的 cDC1 细胞中是否具有其他功能。一个转基因 -Venus 报告基因等位基因增加了 IRF8 蛋白浓度，足以在 小鼠的脾脏中允许自主的 cDC1 发育。这些恢复的 cDC1 在转录上与对照野生型 cDC1 相似，但表达受限的一组 cDC1 特异性基因减少。恢复的 cDC1 能够交叉呈递细胞相关抗原 和 然而， cDC1 表现出改变的特征，并且无法介导肿瘤排斥。这些结果表明，BATF3 除了调节 表达以稳定 cDC1 谱系的分化外，还控制一组用于 cDC1 介导的肿瘤排斥的小基因的表达。这些 BATF3 调节的基因可能是针对促进肿瘤排斥的免疫疗法的有用靶点。
