Additive Effect of CD73 Inhibitor in Colorectal Cancer Treatment With CDK4/6 Inhibitor Through Regulation of PD-L1.

Abstract

BACKGROUND & AIMS:

Although cancer immunotherapies are effective for advanced-stage cancers, there are no clinically approved immunotherapies for colon cancers (CRCs). Therefore, there is a high demand for the development of novel therapies. Extracellular adenosine-mediated signaling is considered a promising target for advanced-stage cancers that are nonresponsive to programmed death 1 (PD-1)-/programmed death-ligand 1 (PD-L1)-targeted immunotherapies. In this study, we aimed to elucidate novel tumorigenic mechanisms of extracellular adenosine.

METHODS:

To investigate the effects of extracellular adenosine on tumor-associated macrophages, peripheral blood-derived human macrophages were treated with adenosine and analyzed using flow cytometry and Western blot. Changes in adenosine-treated macrophages were further assessed using multi-omics analysis, including total RNA sequencing and proteomics. Colon cancer mouse models were used to measure the therapeutic efficacy of AB680 and palbociclib. We also used tissue microarrays of patients with CRC, to evaluate their clinical relevance.

RESULTS:

Extracellular adenosine-mediated reduction of cyclin D1 (CCND1) was found to be critical for the regulation of immune checkpoint molecules and PD-L1 levels in human macrophages, indicating that post-translational modification of PD-L1 is affected by adenosine. A potent CD73 selective inhibitor, AB680, reversed the effects of adenosine on CCND1 and PD-L1. This result strongly suggests that AB680 is a combinatory therapeutic option to overcome the undesired side effects of the cyclin-dependent kinase 4/6 inhibitor, palbociclib, which increases PD-L1 expression in tumors. Because palbociclib is undergoing clinical trials for metastatic CRC in combination with cetuximab (clinical trial number: NCT03446157), we validated that the combination of AB680 and palbociclib significantly improved anti-tumor efficacy in CRC animal models, thereby highlighting it as a novel immunotherapeutic strategy. We further assessed whether the level of CCND1 in tumor-associated macrophages was indeed reduced in tumor sections obtained from patients with CRC, for evaluating the clinical relevance of this strategy.

CONCLUSIONS:

In this study, we demonstrated that a novel combination therapy of AB680 and palbociclib may be advantageous for the treatment of CRC.

• Authors: Ji-Yoon Noh, In Pyo Lee, Na Rae Han, Miok Kim, Yong Ki Min, Sang-Yeop Lee, Sung Ho Yun, Seung Il Kim, Tamina Park, Hyunmin Chung, Daeui Park, Chang Hoon Lee
• Journal: Cellular and molecular gastroenterology and hepatology (Cell Mol Gastroenterol Hepatol) Vol. 14 Issue 4 Pg. 769-788 ( 2022) ISSN: 2352-345X [Electronic] United States
• PMID: 35843546 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• B7-H1 Antigen
• CD274 protein, human
• Immune Checkpoint Proteins
• Programmed Cell Death 1 Receptor
• Cyclin D1
• CDK4 protein, human
• Cyclin-Dependent Kinase 4
• Adenosine
• Cetuximab

Topics

• Adenosine (pharmacology, therapeutic use)
• Animals
• B7-H1 Antigen (metabolism)
• Cetuximab
• Colorectal Neoplasms (genetics)
• Cyclin D1
• Cyclin-Dependent Kinase 4
• Humans
• Immune Checkpoint Proteins
• Mice
• Programmed Cell Death 1 Receptor