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.

Yosuke Osawa,Shigenori Osakaya,Tatsuya Kanto,Ekumi Kojika,Yutaka Kawakami,Kiminori Kimura,Hiromi Miyauchi,Masamichi Kimura,Koji Nishikawa

doi:10.18632/oncotarget.26892

Abstract

ABSTRACTImmune 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+CD44lowCD62Llow 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.

Highlights

Immune checkpoint blockade has been reported to have anti-cancer effects with antibodies (Abs) against programmed cell death 1 (PD-1) and programmed deathligand 1 (PD-L1) being effective in types of several cancer [1,2,3]
Activation of β-catenin induces the expression of the transcriptional repressor AMP-dependent transcription factor-3 (ATF3), which suppresses the production of C-C motif chemokine ligand-4 (CCL4), leading to T-cell exclusion [6]
In contrast, the combination treatment with both agents significantly reduced liver weight and Ki67-positive area (Figure 1A, 1B). These results suggested that the co-administration of PRI-724 and PD-L1 Ab was able to exert an anti-tumor effect on SL4 cell metastasis to the liver

Summary

Introduction

Immune checkpoint blockade has been reported to have anti-cancer effects with antibodies (Abs) against programmed cell death 1 (PD-1) and programmed deathligand 1 (PD-L1) being effective in types of several cancer [1,2,3]. The expression level of PD-1 ligands is increased in various cancers, resulting in cancer cell resistance to elimination by tumor-specific T cells [1]. The anti-tumor activity of an anti-PD-1 Ab has been observed in nonsmall cell lung cancer, melanoma, and renal cell cancer; no response was observed in colorectal cancer [2]. The anti-tumor activity of an anti-PD-L1 Ab was observed in melanoma, non-small cell lung cancer, renal cell cancer, and ovarian cancer, but no response was observed in colorectal cancer [4]. Tumor regression based on the anti-tumor effects of an anti-PD-1 Ab requires the presence of CD8+ T-cells in the tumor [5] and activation of the β-catenin pathway in the tumor is inversely correlated with the www.oncotarget.com extent of CD8+ T-cell infiltration [6]. Activation of β-catenin induces the expression of the transcriptional repressor AMP-dependent transcription factor-3 (ATF3), which suppresses the production of C-C motif chemokine ligand-4 (CCL4), leading to T-cell exclusion [6]

Methods

Results

Conclusion