Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland; Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Department of Biomedicine, University Hospital Basel and University of Basel, 4031 Basel, Switzerland.
Cell Rep. 2019 Sep 24;28(13):3367-3380.e8. doi: 10.1016/j.celrep.2019.08.057.
Dendritic cell (DC) activation is a critical step for anti-tumor T cell responses. Certain chemotherapeutics can influence DC function. Here we demonstrate that chemotherapy capable of microtubule destabilization has direct effects on DC function; namely, it induces potent DC maturation and elicits anti-tumor immunity. Guanine nucleotide exchange factor-H1 (GEF-H1) is specifically released upon microtubule destabilization and is required for DC activation. In response to chemotherapy, GEF-H1 drives a distinct cell signaling program in DCs dominated by the c-Jun N-terminal kinase (JNK) pathway and AP-1/ATF transcriptional response for control of innate and adaptive immune responses. Microtubule destabilization, and subsequent GEF-H1 signaling, enhances cross-presentation of tumor antigens to CD8 T cells. In absence of GEF-H1, anti-tumor immunity is hampered. In cancer patients, high expression of the GEF-H1 immune gene signature is associated with prolonged survival. Our study identifies an alternate intracellular axis in DCs induced upon microtubule destabilization in which GEF-H1 promotes protective anti-tumor immunity.
树突状细胞 (DC) 的激活是抗肿瘤 T 细胞反应的关键步骤。某些化疗药物会影响 DC 的功能。在这里，我们证明了能够破坏微管的化疗药物对 DC 功能有直接影响；即，它诱导强烈的 DC 成熟并引发抗肿瘤免疫。鸟嘌呤核苷酸交换因子-H1（GEF-H1）在微管不稳定时特异性释放，是 DC 激活所必需的。对化疗的反应中，GEF-H1 在 DC 中驱动独特的细胞信号转导程序，该程序主要由 c-Jun N 端激酶 (JNK) 途径和 AP-1/ATF 转录反应主导，用于控制先天和适应性免疫反应。微管的不稳定，以及随后的 GEF-H1 信号，增强了肿瘤抗原对 CD8 T 细胞的交叉呈递。在没有 GEF-H1 的情况下，抗肿瘤免疫受到阻碍。在癌症患者中，GEF-H1 免疫基因特征的高表达与延长的生存时间相关。我们的研究确定了微管不稳定诱导的 DC 中的另一个细胞内轴，其中 GEF-H1 促进了保护性的抗肿瘤免疫。
