Downregulated expression of the cancer stem cells marker CD47 induced by 4-Methylumbelliferone promoted phagocytosis by antigen presenting cells and stimulated specific T cell response against hepatocellular carcinoma.

RODRIGUEZ, MARCELO M.; MARIANA MALVICINI; ESTEBAN FIORE; JUAN BAYO; AGOSTINA ONORATO; LUCIANA DOMINGUEZ; CATALINA ATORRASAGASTI; MARIANA GARCIA; GUILLERMO MAZZOLINI

Congreso; LIII Reunion Anual de la Sociedad Argentina de Investigacion Clinica; 2018

Sociedad Argentina de Investigación Clínica

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 immune escape and sustains tumor growth. We previously demonstrated that the hyaluronan synthesis inhibitor 4-methylumbelliferone (4Mu) combined with an adenovirus encoding interleukin-12 genes (AdIL-12) showed a potent antitumor effect, increased animal survival and achieves a successful antitumor immune response in an orthotopic HCC established in fibrotic livers. Our aim was to investigate why 4Mu boosted the immune response and induces antitumor activity in HCC. We evaluated if 4Mu facilitates tumor recognition and phagocytosis by in vitro phagocytosis assays using intraperitoneal macrophages. We also analyzed the expression of CSCs markers, particularly CD47+, and isolated CSCs by magnetic separation of CD133+ cells. We found that 4Mu downregulated the expression of the CSCs marker CD47+ within HCC tumors, promoted phagocytosis by antigen presenting cells and, combined with Ad-IL12, induced a potent cytotoxic specific T cell response against HCC. We also observed a significantly decrease in hepatic mRNA levels of CD133+, CD90+, EpCAM+, CD44+ and CD13+ CSCs markers (p