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Biomedicine & Pharmacotherapy
journal homepage: www.elsevier.com/locate/biopha
Basing on uPAR-binding fragment to design chimeric antigen receptors triggers antitumor eﬃcacy against uPAR expressing ovarian cancer cells
Liang Wang, Rulin Yang, Liping Zhao, Xiwen Zhang, Tianmin Xu , Manhua Cui
Department of Gynecology and Obstetrics, the Second Hospital of Jilin University, Changchun, 130041, Jilin, China
Chimeric antigen receptor Eﬀector to target ratio
Due to the success of chimeric antigen receptors (CARs) in hematological tumors, CARs are also being studied to treat solid tumors. Improving the ability of CARs to penetrate solid tumor tissues is one of the biggest challenges. As the most malignant cancer of the female reproductive system, the survival rate of ovarian cancer has not been significantly improved by traditional therapy methods; therefore, it is necessary to develop new therapeutic targets and new immunotherapy methods for ovarian cancer. UPAR is a glysocylphosphatidylinositol (GPI) anchoring membrane protein that is diﬀerentially expressed in normal tissues and ovarian cancer tissues. It has been shown that uPAR up-regulation promotes tumor development, proliferation, invasion, and metastasis, and uPAR is also up-regulated in tumor matrix components. In our study, CARs were designed using the natural ligand binding fragment of uPAR for ovarian cancer.
Ovarian cancer is the most malignant gynecologic cancer and its transcoelomic Digitonin is often responsible for substantial morbidity and mortality . The early detection of ovarian cancer remains challenging because clinically obvious symptoms only manifest during the later stages of the disease. Consequently, the ovarian cancer sur-vival rate has not changed significantly despite decades of research . Novel therapeutic methods targeting key cancer characteristics are therefore essential for treating ovarian cancer.
CARs have had successful outcomes in hematopoietic malignancies, inspiring similar strategies to treat solid tumors. CAR is a synthetic receptor that contains an antigen recognition domain, usually a single chain variable fragment (scFv) that binds to a tumor-associated antigen (TAA), a hinge region, a transmembrane domain, and a signaling do-main via co-stimulatory domains to activate cytotoxic functions not constrained by major histocompatibility complex (MHC). The im-munosuppressive nature of the tumor microenvironment prevents the function of CAR against solid tumors. Immune-checkpoint blockade combined with CAR T cells (e.g., anti-PD-1, anti-PD-L1, anti-TIM-3, anti-LAG-3 antibodies, especially anti-PD-1 antibodies) has greatly improved the treatment of solid tumors by preventing the im-munosuppressive function of the cancer immune system . The strategy of immune-checkpoint blockade is based on immune system
against cancer immunosuppression, similarly, considering the com-plexity of solid cancer tissue mass, killing both cancer cells and non-neoplastic stromal cells could overcome the physical barriers in solid tumors to improve traﬃcking and infiltration of CAR T cells .
There are many preclinical studies and clinical trials targeting ovarian cancer and TAAs identified for ovarian cancers includes α-Folate Receptor, Her-2, mesothelin, MUC 16 and epithelial cell adhe-sion molecule (EpCAM), NKG2D, and CD70 . Urokinase; plasmi-nogen activator receptor (uPAR), which is covalently connected to the cell membrane via a glysocylphosphatidylinositol (GPI) anchor, has been clearly shown to be specifically expressed in ovarian cancer tissues but not in the surrounding normal tissues . Rare uPAR expression in some macrophages, some endothelial cells and respiratory epithelial cells is restricted to processes such as tissue remodeling, wound healing, and the inflammatory response, making uPAR an ideal target for CAR T cell therapy [7–9]. UPAR is the receptor for uPA and is involved in the conversion of plasminogen to plasmin, which degrades the extracellular matrix during tumor migration and metastasis and uPAR also aﬀects other signals which induce tumorigenesis, tumor proliferation and ad-hesion, and tumor dormancy and reactivation in ovarian cancer [10,11]. Interestingly, the expression of uPAR on either non-neoplastic stromal cells, cancer cells, or both makes uPAR a promising target for overcoming the physical barriers in ovarian cancer by using by CAR T cell therapy . As a candidate antigen for CAR T cells, the risk of ‘on-