Targeting LTA4H facilitates the reshaping of the immune microenvironment mediated by CCL5 and sensitizes ovarian cancer to Cisplatin
Targeting LTA4H facilitates the reshaping of the immune microenvironment mediated by CCL5 and sensitizes ovarian cancer to Cisplatin
复制标题
DOI：
10.1007/s11427-023-2444-5
复制
发表时间：
2024-01-25
影响因子：
9.1
通讯作者：
Xue，Lixiang
中科院分区：
文献类型：
--
作者：
Guo，Zhengyang;Huang，Jiaqi;Xue，Lixiang
卵巢癌是最致命和最具侵袭性的妇科癌症，复发率高，通常诊断较晚。在卵巢癌中，脂质代谢的多种代谢酶异常表达，导致代谢紊乱。花生四烯酸（AA）是多不饱和脂肪酸（PUFA）代谢的特征性途径，在卵巢癌中存在代谢紊乱。因此，我们建立了一个10基因签名模型来评估PUFA相关基因的预后风险。这种10基因签名具有很强的鲁棒性，可以在各种平台（TCGA，ICGC和GSE 17260）的数据集中发挥稳定的预测作用。风险亚组与临床特征之间的高度相关性表明该模型的性能良好。我们的数据进一步表明，LTA 4 H的高表达与卵巢癌的不良预后呈正相关。LTA 4 H的缺乏增强了对顺铂的敏感性，并改变了卵巢癌中免疫细胞浸润的特征。此外，我们的研究结果表明，CCL 5参与AA/LTA 4 H轴的异常代谢，这有助于减少肿瘤浸润的CD 8 +T细胞和卵巢癌中的免疫逃逸。这些发现为LTA 4 H/CCL 5治疗卵巢癌的预后和潜在靶点提供了新的见解。
Ovarian cancer is the most lethal and aggressive gynecological cancer with a high recurrence rate and is often diagnosed late. In ovarian cancer, multiple metabolic enzymes of lipid metabolism are abnormally expressed, resulting in metabolism disorder. As a characteristic pathway in polyunsaturated fatty acid (PUFA) metabolism, arachidonic acid (AA) metabolism is disturbed in ovarian cancer. Therefore, we established a 10-gene signature model to evaluate the prognostic risk of PUFA-related genes. This 10-gene signature has strong robustness and can play a stable predictive role in datasets of various platforms (TCGA, ICGC, and GSE17260). The high association between the risk subgroups and clinical characteristics indicated a good performance of the model. Our data further indicated that the high expression of LTA4H was positively correlated with poor prognosis in ovarian cancer. Deficiency of LTA4H enhanced sensitivity to Cisplatin and modified the characteristics of immune cell infiltration in ovarian cancer. Additionally, our results indicate that CCL5 was involved in the aberrant metabolism of the AA/LTA4H axis, which contributes to the reduction of tumor-infiltrating CD8+T cells and immune escape in ovarian cancer. These findings provide new insights into the prognosis and potential target of LTA4H/CCL5 in treating ovarian cancer.