Department of Obstetrics and Gynecology, Xijing Hospital, Fourth Military Medical University, No.127 Changle Road (West), Xi'an City, Shannxi Province, 710032, China.
Department of Obstetrics and Gynecology, Xijing Hospital, Fourth Military Medical University, No.127 Changle Road (West), Xi'an City, Shannxi Province, 710032, China.
Exp Cell Res. 2021 May 1;402(1):112522. doi: 10.1016/j.yexcr.2021.112522. Epub 2021 Mar 23.
Immune escape is the main cause of the low response rate to immunotherapy for cancer, including ovarian cancer. Growth differentiation factor-15 (GDF-15) inhibits immune cell function. However, only few reports described the mechanism. Therefore, the aim of this study was to investigate the mechanism of immune escape regulated by GDF-15 in ovarian cancer. Ovarian cancer patients and healthy women were enrolled in this study. Immunohistochemistry and ELISA were performed to measure GDF-15 expression. Immunoprecipitation combined with mass spectrometry, surface plasmon resonance, and co-immunoprecipitation assay were used to evaluate the interaction between GDF-15 and the surface molecules of DCs. Immunofluorescence analysis, flow cytometry and transwell assay were used to evaluate additional effects of GDF-15 on DCs. The results showed that GDF-15 expression was higher in the ovarian cancer patients compared to that in the healthy women. The TIMER algorithm revealed that highly GDF-15 expression is associated with immune DC infiltration in immunoreactive high-grade serous carcinoma. A further study showed that GDF-15 suppressed DCs maturation, as well as IL-12p40 and TNF-α secretion, the length and number of protrusions and the migration. More importantly, CD44 in the surface of DCs interacted with GDF-15. The overexpression of CD44 in DCs resulted in the suppression of the inhibitory effect of GDF-15 on the length and number of DC synapses. In DCs overexpressing CD44 the inhibition of GDF-15 on the expression of CD11c, CD83 and CD86 was decreased, while in DCs with a knockdown of CD44 the inhibition was further enhanced. Knockdown of CD44 in DCs enhanced the inhibitory effect of GDF-15 on DC migration, while the overexpression of CD44 inhibited the inhibitory effect of GDF-15 on DC migration. In conclusion, the present study suggested that GDF-15 might facilitate ovarian cancer immune escape by interacting with CD44 in DCs to inhibit their function.
免疫逃逸是癌症免疫治疗反应率低的主要原因，包括卵巢癌。生长分化因子 15（GDF-15）抑制免疫细胞功能。然而，仅有少数报道描述了其机制。因此，本研究旨在探讨 GDF-15 调节卵巢癌免疫逃逸的机制。本研究纳入了卵巢癌患者和健康女性。通过免疫组化和 ELISA 检测 GDF-15 的表达。采用免疫沉淀结合质谱、表面等离子体共振和共免疫沉淀检测 GDF-15 与 DC 表面分子的相互作用。采用免疫荧光分析、流式细胞术和 Transwell 检测 GDF-15 对 DC 的其他影响。结果显示，卵巢癌患者的 GDF-15 表达高于健康女性。TIMER 算法显示，高 GDF-15 表达与免疫反应性高级别浆液性癌中的免疫 DC 浸润相关。进一步研究表明，GDF-15 抑制 DC 成熟以及 IL-12p40 和 TNF-α 的分泌、突起的长度和数量以及迁移。更重要的是，DC 表面的 CD44 与 GDF-15 相互作用。CD44 在 DC 中的过表达导致 GDF-15 对 DC 突触长度和数量的抑制作用减弱。在过表达 CD44 的 DC 中，GDF-15 对 CD11c、CD83 和 CD86 表达的抑制作用减弱，而在敲低 CD44 的 DC 中，抑制作用进一步增强。在 DC 中敲低 CD44 增强了 GDF-15 对 DC 迁移的抑制作用，而过表达 CD44 抑制了 GDF-15 对 DC 迁移的抑制作用。综上所述，本研究表明，GDF-15 可能通过与 DC 中的 CD44 相互作用来抑制其功能，从而促进卵巢癌的免疫逃逸。
