4-methylumbelliferone (4Mu) overcomes tumor progression mediated by hypoxia and improves the efficacy of immunotherapy in preclinical models of gastrointestinal tumors

MARIANA MALVICINI; ESTEBAN FIORE; JUAN BAYO; MARIANA GARCIA ; CATALINA ATORRASAGASTI; ARANTZA AZPILICUETA LUSARRETA ; IGNACIO MELERO; GUILLERMO MAZZOLINI

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

Hypoxia drives essential adaptations for tumor cells survival including metabolism alteration, pH regulation, epithelial-mesenchymal transition, angiogenesis and evasion of the immune response. Hypoxic cells increase their survival by regulating pH, through the modulation of extracellular carbonic anhydrases (CAIX and CAXII). Hypoxia also induces immune suppressor cells and tumor-associated macrophages (TAMs) infiltration and stimulates the expression of Programmed Death-Ligand 1 (PD-L1) in tumors, suppressing the activity of T cells. We have shown that coumarin 4-methylumbelliferone (4Mu) decreases intratumoral pressure and modify the balance of angiogenic/antiangiogenic factors. Our aims were to evaluate the expression of hypoxia-inducible factor 1 (HIF-1), CAIX, CAXII and changes on tumor microenvironment in preclinical models of gastrointestinal tumors.We analyzed the in vitro expression of CAIX, CAXII and HIF-1 by qPCR in colon adenocarcinoma (CRC) and hepatocellular carcinoma (HCC) cells. We also analyzed the effect of 4Mu on CAIX, CAXII, HIF-1, Arginase 1 (Arg1), inducible Nitric Oxide Sintetase (iNOS), indoleamine dioxygenase (IDO), transforming growth factor beta (TGF-b), interleukin 10 (IL-10) and interleukin 1b (IL-1b) and F4/80 + cells in tumor samples. Then, we evaluate the in vivo efficacy of 4Mu plus the checkpoint inhibitor monoclonal antibody antiPD-1. CRC and HCC cells express carbonic anhydrases and their expression were reduced in presence of 4Mu (p