Growth differentiation factor-15 promotes immune escape of ovarian cancer via targeting CD44 in dendritic cells
Growth differentiation factor-15 promotes immune escape of ovarian cancer via targeting CD44 in dendritic cells
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DOI：
10.1016/j.yexcr.2021.112522
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发表时间：
2021-03-31
影响因子：
3.7
通讯作者：
Chen, Biliang
中科院分区：
文献类型：
--
作者：
Gao, Yunge;Xu, Ying;Chen, Biliang
免疫逃逸是包括卵巢癌在内的癌症免疫治疗应答率低的主要原因。生长分化因子-15（GDF-15）抑制免疫细胞功能。然而，只有少数报告介绍了这一机制。因此，本研究的目的是探讨GDF-15在卵巢癌中调节免疫逃逸的机制。卵巢癌患者和健康女性入选本研究。免疫组化和ELISA法检测GDF-15的表达。采用免疫沉淀结合质谱、表面等离子体共振和免疫共沉淀技术研究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法评价GDF-15对DC的额外作用。结果显示，GDF-15在卵巢癌患者中的表达高于健康女性。TIMER算法显示，在免疫反应性高级别浆液性癌中，GDF-15的高表达与免疫DC浸润相关。进一步的研究表明，GDF-15抑制DC成熟，以及IL-12 p40和TNF-α分泌，突起的长度和数量以及迁移。更重要的是，DC表面的CD 44与GDF-15相互作用。DC中CD 44的过表达导致GDF-15对DC突触长度和数量的抑制作用的抑制。在过表达CD 44的DC中，GDF-15对CD 11 c、CD 83和CD 86表达的抑制降低，而在敲低CD 44的DC中，抑制进一步增强。DCs中CD 44的敲低增强了GDF-15对DC迁移的抑制作用，而CD 44的过表达则抑制了GDF-15对DC迁移的抑制作用。本研究提示GDF-15可能通过与DC中的CD 44相互作用抑制其功能而促进卵巢癌的免疫逃逸。
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-alpha 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.