Exosomal CD47 plays an essential role in immune evasion in ovarian cancer.

Ovarian cancer (OC) is largely diagnosed at advanced stages upon detection of multiple peritoneal dissemination, resulting in poor outcomes. CD47 is overexpressed in tumors, facilitates tumor immune evasion, and is located on exosomes. We aimed to investigate the role of exosomal CD47 in OC progression. Prognostic significance of CD47 expression in OC was examined using a public database including 1,435 patients and validated with 26 patients at our institution. CD47 expression was associated with poor progression-free survival and inversely correlated with macrophage infiltration in OC tissues. Exosomes were collected from OC cell lines, and CD47 expression on exosomes was confirmed via flow cytometry. Inhibition of exosome secretion with GW4869 and exosome uptake with EIPA inhibited the surface CD47 expression on OC cells and promoted phagocytosis by macrophages. RAB27A (a key regulator of exosome release) knockdown inhibited exosome secretion and led to CD47 downregulation in OC cells. In a xenograft mouse model. Suppression of the release of tumor-derived exosomes by GW4869 or RAB27A knockdown suppressed tumor progression and enhanced M1 macrophage phagocytosis in cancer tissues. Collectively, CD47 expression was correlated with poor prognoses in OC patients, suggesting the importance of immune evasion. CD47 was expressed on exosomes and the inhibition of exosome secretion and/or uptake enhanced cancer cell phagocytosis by macrophages, and thus, suppressed peritoneal dissemination. This suggests the potential of a novel immune checkpoint therapeutic agent that focuses on exosomes. Implications: Mechanistic insight from the current study suggests that exosomal CD47 may be an advantageous therapeutic target in ovarian cancer.