Epithelial ovarian cancer is one of the leading causes of death from gynecological malignancies worldwide, with a high recurrence rate and poor clinical outcomes (Itamochi et al., 2008, Sambasivan, 2022). Epithelial ovarian cancer is a heterogeneous disease often classified into four major histological subtypes: serous, mucinous, endometrioid, and clear cell carcinoma (Torre et al., 2018). Notably, a higher incidence of ovarian clear cell carcinoma (OCCC) is observed in East Asian populations, particularly in Japan (Fujiwara et al., 2016, Lee et al., 2019, Hao et al., 2021). Additionally, there is a trend toward developing OCCC at a younger age, which has been rising in recent decades (Torre et al., 2018, Machida et al., 2019, Gan et al., 2023). Despite the fact that patients with OCCC are frequently diagnosed at an early stage, the prognosis of OCCC is extremely poor than other histological types (Sugiyama et al., 2000, Itamochi et al., 2008) due to less sensitivity to platinum-based first-line chemotherapy (Itamochi et al., 2008, Takano et al., 2012).

Recently, immune checkpoint inhibitors targeting immune checkpoint molecules such as programmed death ligand-1 (PD-L1) and the PD-1 axis have provided excellent treatment outcomes in patients with a wide variety of cancer cell types (Nixon et al., 2018, Naumann et al., 2019). However, the response rates to anti-PD-L1 antibodies (Abs) in patients with OCCC are considerably low because the expression levels of PD-L1 are low in the tumor tissue of OCCC (Hamanishi et al., 2015, Oda et al., 2018, Disis et al., 2019). Hence, urgent efforts are needed to develop a novel therapeutic approach for OCCC.

CD47 is a transmembrane protein expressed by myeloid cells such as erythrocytes and leukocytes that inhibits phagocytosis by binding to signal regulatory protein (SIRP) α present on the macrophage (Logtenberg et al., 2020, Liu et al., 2023). CD47 is also highly expressed in almost all cancer cells and participates in immune evasion by escaping of cancer cells from macrophage phagocytosis through the “don’t eat me” signal, leading to excessive tumor growth (Logtenberg et al., 2020, Liu et al., 2023). Interestingly, patients with ovarian cancers have an extremely high CD47 expression in tumor tissues, associated with decreased survival rate (Liu et al., 2017, Shimizu et al., 2021, Yu et al., 2021a). Therefore, the innate immune checkpoint inhibition targeting CD47-SIRPα may be a promising novel cancer immunotherapy.

Ezrin-Radixin-Moesin (ERM) family member of proteins connect certain cell surface transmembrane proteins with the actin cytoskeleton, leading to their cell surface localization and functional activity (Asp et al., 2016, Ogihara et al., 2020). We recently found that ERM works as a scaffold protein to regulate the cell surface localization of PD-L1 in several gynecologic cancer cell lines (Tameishi et al., 2021, Tanaka et al., 2021, Doukuni et al., 2022, Kobori, 2022, Tameishi et al., 2022, Tanaka et al., 2022), including OCCC (Kobori et al., in press). However, it is yet to be determined whether ERM serves to control the plasma membrane expression of CD47, which is an immunoglobulin (IgG) superfamily similar to PD-L1 in OCCC. In this study, we investigated the role of ERM family in the plasma membrane localization and the functional activity of CD47 using cell lines derived from Japanese patients with OCCC.