GALECTINS AS NOVEL THERAPEUTIC TARGETS

GABRIEL A RABINOVICH

Buenos Aires, Argentina

Workshop; Primer Workshop Argentino-Germano sobre tratamientos celulares y moleculares para Cáncer y Enfermedades Degenerativas; 2005

Fundación ARGER, ANMAT, CONICET, SECYT, CEDIQUIFA

GALECTINS AS NOVEL THERAPEUTIC TARGETS   Galectins belong to a family of animal lectins with affinity for beta galactoside sugars. They mediate cell signal transduction pathways that may induce apoptosis or differentiation, depending on the type of cell . Galectin 1 (Gal-1), a homodimer composed by subunits of 14.5 kDa, promotes apoptosis of T-activated lymphocytes but not on resting T lymphocytes. However, it also sensitizes T-cells to FAS ligand and it is  expressed by cells from primary and metastatic melanoma. Rabinovich and colleagues generated the hypothesis that tumors cells evade the immune response by  secretion of Gal-1 . Using a combination of in vitro and in vivo  experiments The authors demonstrated that Gal-1 contributes  to immune privilege of tumors by modulating survival and differentiation > of effector cytotoxic T lymphocytes. .  To estimate the tumor immunosupresive potential of gal-1, Rabinovich  designed a series of ingenious experiments. First, he activated T cells  with anti-CD3 or phytohemoagglutinin (PHA), and incubated them with  melanoma supernatants containing every possible immunosupressive factor  produced by this type of tumor. As a result, 75% of activated T cells went  apoptotic. Then the experiment was repeated, but adding an anti-gal-1  antibody, and the number of apoptotic T cells went down to 26%. Then, to  test the idea in vivo, the authors subcloned antisense gal-1 and used it to  create three different classes of B16 melanoma cells differing in the  levels of gal-1 (high, intermediate and low). When the supernatants of  these three different cultures met activated T cells, the apoptotic  turnover was 61%, 40% and 27%, respectively.  In the next experiments the authors injected them in C57 syngeneic animals.  The high-level group showed very rapid tumor growth. But the tumor masses expressing the lowest levels of gal-1 showed very little growth after day 36.  The authors also isolated lymph nodes of animals that had received  antisense therapy, and evaluated proliferation and cytokines. Lymph nodes  from animals with low gal-1 expressing tumours had a low proliferation,  and produced high levels of IL2 and gamma IFN; but no level changes in IL4  and IL5 were noticed. So, blocking gal-1 unrepresses an IFN-gamma-mediated > response, whereas expression of gal-1 switches the system into a T helper  2 (TH2) response. Rabinovich and colleagues checked in mice whether the tissue expressión of  gal-1 correlated with high levels of apoptosis of infiltrating lymphocytes, and of the tumor itself. The tumors that expressed high  levels of gal-1 had a large number of infiltrating apoptotic T  lymphocytes. However, the tumors that expressed low level of gal-1 did  not. But the tumors themselves were getting apoptotic: cytotoxic T  lymphocytes proliferating within them were wiping them out with high > levels of IFN-gamma production. Thus, the investigators concluded that  galectin-1 is a key regulator of tumor-immune escape by tilting the  balance toward an immunosuppressive environment at the tumor site. The group is currently investigating the molecular bases of this effect, the  impact of differential glycosylation in this mechanism, effect of Gal-1  on different immune cell types and the search of potential inhibitors of  tumor escape and metastasis based on protein-glycan interactions.