PDF(Pubmed)
Abstract：
Tumor cells reprogram their metabolism to produce specialized metabolites that both fuel their own growth and license tumor immune evasion. However, the relationships between these functions remain poorly understood. Here, we report CRISPR screens in a mouse model of colo-rectal cancer (CRC) that implicates the dual specificity phosphatase 18 (DUSP18) in the establishment of tumor-directed immune evasion. Dusp18 inhibition reduces CRC growth rates, which correlate with high levels of CD8+ T cell activation. Mechanistically, DUSP18 dephosphorylates and stabilizes the USF1 bHLH-ZIP transcription factor. In turn, USF1 induces the SREBF2 gene, which allows cells to accumulate the cholesterol biosynthesis intermediate lanosterol and release it into the tumor microenvironment (TME). There, lanosterol uptake by CD8+ T cells suppresses the mevalonate pathway and reduces KRAS protein prenylation and function, which in turn inhibits their activation and establishes a molecular basis for tumor cell immune escape. Finally, the combination of an anti-PD-1 antibody and Lumacaftor, an FDA-approved small molecule inhibitor of DUSP18, inhibits CRC growth in mice and synergistically enhances anti-tumor immunity. Collectively, our findings support the idea that a combination of immune checkpoint and metabolic blockade represents a rationally-designed, mechanistically-based and potential therapy for CRC.
摘要：
肿瘤细胞重新编程其代谢以产生专门的代谢产物，这些代谢产物既促进了自身的生长，又允许肿瘤免疫逃避。然而,这些函数之间的关系仍然知之甚少。这里,我们报道了在结肠直肠癌(CRC)小鼠模型中进行的CRISPR筛选,该筛选提示双特异性磷酸酶18(DUSP18)参与了肿瘤定向免疫逃避的建立.Dusp18抑制降低CRC生长速率，这与高水平的CD8+T细胞活化相关。机械上,DUSP18去磷酸化并稳定USF1bHLH-ZIP转录因子。反过来,USF1诱导SREBF2基因，它允许细胞积累胆固醇生物合成中间体羊毛甾醇并将其释放到肿瘤微环境（TME）中。在那里,CD8+T细胞摄取羊毛甾醇抑制甲羟戊酸途径，降低KRAS蛋白戊烯化和功能，这反过来又抑制了它们的激活，并建立了肿瘤细胞免疫逃逸的分子基础。最后,抗PD-1抗体和Lumacaftor的组合，一种FDA批准的DUSP18小分子抑制剂，抑制小鼠CRC生长并协同增强抗肿瘤免疫力。总的来说，我们的研究结果支持免疫检查点和代谢阻断的组合代表了合理设计的，基于机械和潜在的CRC治疗。
