Programmed cell death ligand 1 (PD-L1) blockade attenuates metastatic colon cancer growth in cAMP-response element-binding protein (CREB)-binding protein (CBP)/β-catenin inhibitor-treated livers

Abstract

// Yosuke Osawa 1 , 2 , Ekumi Kojika 1 , Koji Nishikawa 1 , Masamichi Kimura 1 , Shigenori Osakaya 1 , Hiromi Miyauchi 1 , Tatsuya Kanto 2 , Yutaka Kawakami 3 and Kiminori Kimura 1 1 Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Bunkyo-ku, Tokyo 113-8677, Japan 2 The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa 272-8516, Japan 3 Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan Correspondence to: Kiminori Kimura, email: kkimura@cick.jp Keywords: PD-L1; β-catenin; CBP; colon cancer; metastatic liver cancer Received: November 22, 2018     Accepted: April 14, 2019     Published: April 30, 2019 ABSTRACT Immune checkpoint blockade with specific antibodies can accelerate anti-tumor immunity, resulting in clinical responses in patients with various types of cancer. However, these antibodies achieve only partial tumor regression. Thus, a wide variety of treatment combinations based on programmed death-ligand 1 (PD-L1) pathway inhibition are under development to enhance such therapeutic effects. In this study, the effects of combination treatment using PRI-724, a selective inhibitor of CBP/β-catenin, and an anti-PD-L1 antibody were examined in a mouse model of colon cancer liver metastasis. Mice were inoculated with SL4 colon cancer cells to produce metastatic liver tumors. The combination treatment resulted in regression of tumor growth, whereas monotherapy with each treatment individually failed to exhibit any anti-tumor activity. In addition, co-administration of the inhibitor and antibody induced CD8 + CD44 low CD62L low cells and interferon (IFN)-γ production in CD8 + T-cells in the liver compared with that in control mice. Administration of an anti-CD8 antibody mitigated the anti-tumor effects of the combined treatment of PRI-724 and anti-PD-L1 antibody. In conclusion, targeting CBP/β-catenin, combined with PD-1/PD-L1 immune checkpoint blockade, shows potential as a new therapeutic strategy for treating liver metastasis during colon cancer.