Placenta-derived trophoblast extracellular vesicles promote CD169(+) macrophage migration and suppress ovarian tumour growth.

BACKGROUND: A lower survival rate due to a later stage of diagnosis requires a more effective therapy for ovarian cancer. Extracellular vesicles (EVs) have shown therapeutic potential in various diseases, partly due to their ability to modulate immune responses. We previously showed that placental-derived trophoblast EVs suppressed ovarian tumour growth, accompanied by increased infiltration of CD169(+) macrophages and NK cells in tumours. However, the underlying mechanism is unclear. Here, we investigated how immune cells migrate to tumors in response to placental-derived trophoblast EVs in vivo. METHOD: SKOV-3 ovarian cancer cell xenografts were intraperitoneally injected with placental-derived trophoblast EVs. Tumour growth was monitored, and EV biodistribution was tracked at four time points. Additionally, the dynamics of CD169(+) macrophages and NK cells were analysed in immune organs and tumour tissues. RESULTS: A reduction of tumour growth after EV treatment was observed. At early time points (within 24 hours), trophoblast EVs preferentially accumulated in immune organs, including the inguinal lymph nodes, but not in tumours. The significantly higher intensity of CD169(+) macrophages was observed in the inguinal lymph nodes within 24 hours, compared to controls. However, by day 30, the infiltration of EVs and CD169(+) macrophages was observed in tumours, with clear colocalization. Additionally, no infiltration of NK cells was observed at early time points, but was observed at day 30 in the inguinal lymph nodes, with the increase in IL-15, a known NK cell activator. Importantly, in non-tumour-bearing mice following EV treatment, the infiltration of CD169(+) macrophages in the inguinal lymph nodes was not observed, compared to controls. CONCLUSION: Placental-derived trophoblast EVs may act as an immune modulator, specifically in the presence of tumours, through promoting CD169(+) macrophage recruitment to the tumour site, resulting in an anti-ovarian tumour response. These findings suggest the potential of trophoblast EVs as a novel immune-based therapeutic strategy.