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Growth differentiation factor-15 promotes immune escape of ovarian cancer via targeting CD44 in dendritic cells
Yunge Gao1, Ying Xu1, Shuhui Zhao1
1Department of Obstetrics and Gynecology, Xijing Hospital, Fourth Military Medical University, No.127 Changle Road (West), Xi'an City, Shannxi Province, 710032, China.
Abstract:
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.
Insights
Growth differentiation factor-15 (GDF-15) promotes ovarian cancer immune escape by inhibiting dendritic cell (DC) function through interaction with CD44. This study elucidates a key mechanism of immunotherapy resistance in ovarian cancer.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Immune escape significantly limits immunotherapy response in cancers like ovarian cancer.
- Growth differentiation factor-15 (GDF-15) is known to inhibit immune cell function, but its precise role in ovarian cancer immune escape remains unclear.
Purpose of the Study:
- To investigate the mechanism by which GDF-15 mediates immune escape in ovarian cancer.
- To identify the interaction between GDF-15 and dendritic cells (DCs) and its functional consequences.
Main Methods:
- Measured GDF-15 expression in ovarian cancer patients versus healthy controls using immunohistochemistry and ELISA.
- Utilized immunoprecipitation-mass spectrometry, surface plasmon resonance, and co-immunoprecipitation to assess GDF-15 interactions with DC surface molecules.
- Employed immunofluorescence, flow cytometry, and transwell assays to evaluate GDF-15's effects on DC maturation, function, and migration.
Main Results:
- GDF-15 expression was elevated in ovarian cancer patients.
- GDF-15 suppressed DC maturation, cytokine secretion (IL-12p40, TNF-α), protrusion formation, and migration.
- GDF-15 directly interacted with CD44 on DCs, modulating DC function and migration in a CD44-dependent manner.
Conclusions:
- GDF-15 plays a critical role in ovarian cancer immune escape by impairing DC function.
- The interaction between GDF-15 and CD44 on DCs is a key mechanism driving this immunosuppression.
- Targeting the GDF-15/CD44 axis may represent a novel strategy to overcome immunotherapy resistance in ovarian cancer.
