Effect of altered redox potential in tumor immune escape

LAURA GIRIBALDI; DIEGO LADERACH; DANIEL COMPAGNO; LUCAS GENTILINI; IVÁN MASCANFRONI; JUANPABLO CERLIANI; DIEGO CROCCI; MARTA TOSCANO, MARIANA SALATINO, GABRIEL RABINOVICH

Montevideo

Simposio; Symposium Thiol metabolism and redox regulation of celular functions,; 2011

The cellular redox state is controlled by two major systems: the glutathione system and the thioredoxin system, which typically acts as a reductase protein system. In mammals there are two thioredoxin (Trx) proteins: a) the thioredoxin 1 which is confined to the cytosol and the nucleus (the truncate form, Trx80, is secreted), and b) the Trx‐2 which is mainly mitochondrial (Holmgren, Annu Rev Biochem 1985). The redox potential is altered in tumors exposed to hypoxic microenvironments. Moreover, tumors present low mitochondrial respiratory chain (Fukuda et al, Cell 2007) and an increase in the pentose cycle activity (Gatenby et al, Nat Rev Cancer 2004), which promote NADH and NADPH accumulation to create a reducing microenvironment (Hoffmann et al, J Cell Physiol 2001). The Trx system is increased in several types of tumors, including melanoma, colorectal, kidney and lung cancer (LIncoln et al, Anticancer Res 2004; Soini et al, Clin Cancer Res 2001). On the other hand, serum levels of Trx decrease when the tumors are removed (Powis et al, Curr Opin Pharmacol 2007). Futhermore, a rise in the Trx system correlates with an increase in non protein thiols (NPSH) (Guichard et al, Br J Radiol 1990, Ceccarelli et al, Int J Cancer 2008). Galectin‐1, a 14.5 KDa β‐ galactoside‐binding lectin which can form lattices on the cell surface and extracellular matrix to modulate different steps in tumor progression including cell proliferation, adhesion, migration, angiogenesis and tumor‐immune escape. Galectin‐1 levels are higher in many types of tumors where it contributes to the immunosuppressive potential of these cells (Rubinstein et al Cancer Cell 2004; Juczszynski et al, PNAS 2007). In fact, galectin‐1 confers immune privilege to tumors by modulating the fate of Th1 and Th17 effector cells (Toscano et al, Nat Immunol 2007) and instructing dendritic cells toward a tolerogenic phenotype. Interestingly, galectin‐1 is extremelly sensitive to oxidative microenvironments, suggesting that it might serve as an immunosuppressive weapon only under reducing conditions. As melanoma cells exhibit a high reducing potential (Lincoln et al, Anticancer Res 2003) and express substantial levels of galectin‐1 (Rubinstein et al Cancer Cell, 2004), we hypothesize that the typical reducing potential of the tumor microenvironmental provides the adequate redox state required for the immunosuppressive activity of galectin‐1. To prove this hypothesis, we wish to modulate Trx expression in B16 mouse melanoma cells by generating siRNA‐mediated Trx‐1 knockdown clones and to study the effects of altering the redox potential in galectin‐1‐induced immunosuppression.