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Targeting LTA4H facilitates the reshaping of the immune microenvironment mediated by CCL5 and sensitizes ovarian cancer to Cisplatin

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Abstract

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.

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Acknowledgement

This work was supported by the General Program of National Natural Science Foundation of China (82272745, 82072870, 81972966), General Program of Natural Science Foundation of Beijing (7202224), the National Key Research and Development Program of China (2022YFA1104001), Youth Program of National Natural Science Foundation of China (82203102, 82303801) and Peking University Third Hospital Clinical Key Project (BYSY2022069). We are grateful to Prof. Mingxi Zang of Zhengzhou University for providing Bestatin, to Dr. Yifan Chen of Peking University Third Hospital for providing Decitabine, and to the Department of Obstetrics and Gynecology of Peking University Third Hospital for providing samples for pre-experiment of multiplex IHC staining.

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  1. Contributed equally to this work

Authors and Affiliations

  1. Cancer Center of Peking University Third Hospital, Beijing, 100191, China

    Zhengyang Guo, Jiaqi Huang, Xiao Huo, Chen Huang, Xiaotong Yu, Yan Sun, Yanfang Li, Jianling Yang & Lixiang Xue

  2. Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China

    Zhengyang Guo, Xiao Huo, Chen Huang, Xiaotong Yu, Yan Sun, Yanfang Li, Jianling Yang & Lixiang Xue

  3. Peking University Third Hospital Cancer Center, Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China

    Jiaqi Huang & Lixiang Xue

  4. Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, 100191, China

    Tianhui He & Hongyan Guo

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  1. Zhengyang Guo
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  2. Jiaqi Huang
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  4. Chen Huang
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Correspondence to Hongyan Guo, Jianling Yang or Lixiang Xue.

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The author(s) declare that they have no conflict of interest. All sampling and experimental steps In this study were approved by the Ethics Committee of Peking University Third Hospital (License No. M2021013). Informed consent was obtained from all individuals included in this study.

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Guo, Z., Huang, J., Huo, X. et al. Targeting LTA4H facilitates the reshaping of the immune microenvironment mediated by CCL5 and sensitizes ovarian cancer to Cisplatin. Sci. China Life Sci. (2024). https://doi.org/10.1007/s11427-023-2444-5

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