4Mu Decreases CD47 Expression on Hepatic Cancer Stem Cells and Primes a Potent Antitumor T Cell Response Induced by Interleukin-12.

Abstract

The tumor microenvironment (TME) represents a complex interplay between different cellular components, including tumor cells and cancer stem cells (CSCs), with the associated stroma; such interaction promotes tumor immune escape and sustains tumor growth. Several experimental approaches for cancer therapy are focused on TME remodeling, resulting in increased antitumor effects. We previously demonstrated that the hyaluronan synthesis inhibitor 4-methylumbelliferone (4Mu) decreases liver fibrosis and induces antitumor activity in hepatocellular carcinoma (HCC). In this work, 4Mu, in combination with an adenovirus encoding interleukin-12 genes (AdIL-12), elicited a potent antitumor effect and significantly prolonged animal survival (p < 0.05) in an orthotopic HCC model established in fibrotic livers. In assessing the presence of CSCs, we found reduced mRNA levels of CD133+, CD90+, EpCAM+, CD44+, and CD13+ CSC markers within HCC tumors (p < 0.01). Additionally, 4Mu downregulated the expression of the CSC marker CD47+ on HCC cells, promoted phagocytosis by antigen-presenting cells, and, combined with Ad-IL12, elicited a potent cytotoxic-specific T cell response. Finally, animal survival was increased when CD133low HCC cells, generated upon 4Mu treatment, were injected in a metastatic HCC model. In conclusion, the combined strategy ameliorates HCC aggressiveness by targeting CSCs and as a result of the induction of anticancer immunity.

• Authors: Marcelo M Rodríguez, Esteban Fiore, Juan Bayo, Catalina Atorrasagasti, Mariana García, Agostina Onorato, Luciana Domínguez, Mariana Malvicini, Guillermo Mazzolini
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 26 Issue 12 Pg. 2738-2750 (12 05 2018) ISSN: 1525-0024 [Electronic] United States
• PMID: 30301668 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• Biomarkers
• CD47 Antigen
• Interleukin-12
• Hymecromone

Topics

• Animals
• Antigen-Presenting Cells (drug effects, immunology, metabolism)
• Biomarkers
• CD47 Antigen (genetics)
• Carcinoma, Hepatocellular (etiology, metabolism, pathology, therapy)
• Cell Line, Tumor
• Cytotoxicity, Immunologic
• Disease Models, Animal
• Disease Progression
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hymecromone (pharmacology)
• Interleukin-12 (genetics, metabolism)
• Liver Neoplasms (etiology, metabolism, pathology, therapy)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology, metabolism)
• Mice
• Neoplastic Stem Cells (drug effects, metabolism)
• Phagocytosis (immunology)
• T-Lymphocytes (drug effects, immunology, metabolism)
• Tumor Microenvironment (drug effects, genetics, immunology)
• Xenograft Model Antitumor Assays