Targeting the EP1 receptor reduces Fas ligand expression and increases the antitumor immune response in an in vivo model of colon cancer

• Published in: International journal of cancer Vol. 133; no. 4; pp. 825 - 834
• Main Authors: O'Callaghan, Grace, Ryan, Aideen, Neary, Peter, O'Mahony, Caitlin, Shanahan, Fergus, Houston, Aileen
• Format: Journal Article
• Language: English
• Published: Hoboken, NJ Wiley-Blackwell 15.08.2013; Wiley Subscription Services, Inc
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Cancer; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Chemotherapy; Colonic Neoplasms - immunology; Colonic Neoplasms - pathology; Colorectal cancer; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; EP1 receptor; Fas Ligand Protein - metabolism; Female; Flow Cytometry; Gastroenterology. Liver. Pancreas. Abdomen; immune suppression; Ligands; Medical sciences; Mice; Mice, Inbred BALB C; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); PGE2; Real-Time Polymerase Chain Reaction; Receptors, Prostaglandin E, EP1 Subtype - drug effects; Side effects; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Antineoplastic agent; Fas ligand; Immune response; Targeting; Arachidonic acid derivatives; Cytokine; Prostaglandin E2; Increase; Malignant tumor; PGE; Colonic disease; In vivo; Immunosuppression; Colon cancer; Cancerology; EP1 receptor; Tumor necrosis factor; Eicosanoid; Digestive diseases; Intestinal disease; Models; immune suppression; Cancer; Biological receptor
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28076

Despite studies demonstrating that inhibition of cyclooxygenase‐2 (COX‐2)‐derived prostaglandin E2 (PGE2) has significant chemotherapeutic benefits in vitro and in vivo, inhibition of COX enzymes is associated with serious gastrointestinal and cardiovascular side effects, limiting the clinical utility of these drugs. PGE2 signals through four different receptors (EP1–EP4) and targeting individual receptor(s) may avoid these side effects, while retaining significant anticancer benefits. Here, we show that targeted inhibition of the EP1 receptor in the tumor cells and the tumor microenvironment resulted in the significant inhibition of tumor growth in vivo. Both dietary administration and direct injection of the EP1 receptor‐specific antagonist, ONO‐8713, effectively reduced the growth of established CT26 tumors in BALB/c mice, with suppression of the EP1 receptor in the tumor cells alone less effective in reducing tumor growth. This antitumor effect was associated with reduced Fas ligand expression and attenuated tumor‐induced immune suppression. In particular, tumor infiltration by CD4+CD25+Foxp3+ regulatory T cells was decreased, whereas the cytotoxic activity of isolated splenocytes against CT26 cells was increased. F4/80+ macrophage infiltration was also decreased; however, there was no change in macrophage phenotype. These findings suggest that the EP1 receptor represents a potential target for the treatment of colon cancer. What's new? Inhibition of the inflammatory mediator prostaglandin E2 (PGE2) through blockade of cycloxygenase enzyme activity slows tumor growth but also causes severe side effects, a problem that may be bypassed with the identification of alternative anti‐inflammatory drug targets. One such target may be the PGE2 receptor EP1, reported here. Dietary administration and direct injection of the EP1 antagonist ONO‐8713 was found to slow tumor growth in a colon cancer mouse model. Targeting of the EP1 receptor was associated with reduced FasL expression, reduced regulatory T‐cell infiltration, and an improved anti‐tumor immune response.