PROTEIN-CARBOHYDRATE INTERACTIONS IN THE ESTABLISHMENT OF IMMUNE TOLERANCE

G. RABINOVICH

ANGRA DOS REIS

Conferencia; TWAS-ROLAC. FIRST REGIONAL CONFERENCE OF YOUNG SCIENTISTS: PROMOTING LIFE SCIENCES FOR SUSTAINABLE DEVELOPMENT; 2006

THIRD WORLD ACADEMY OF SCIENCE

BACKGROUND: Tumors must circumvent the immune response of the host to become clinically detectable. For this purpose, malignant cells have devised multiple strategies to evade or thwart immune attack. These mechanisms are suggested to conspire in advanced stages of cancer to limit the ability of the immune system to restrain the tumor and the effectiveness of immunotherapy strategies to successfully eradicate malignant cells. We have previously demonstrated that galectin-1 (Gal-1), a glycan-binding protein secreted by several tumors, has the potential to inhibit T-cell effector functions by promoting apoptosis of activated T cells and skewing the balance of the immune response toward a T helper (Th)2 cytokine profile. HYPOTHESIS: On the basis of these data we hypothesized that tumor cells may impair T cell effector functions by secretion of Gal-1 and that this mechanism may contribute in tilting the balance toward an immunosuppressive environment at the tumor site. RESULTS: We demonstrated that tumors can overwhelm T-cell effector functions through Gal-1-dependent mechanisms. By a combination of in vitro and in vivo experiments using knockdown transfectants, we established a link between Gal-1-mediated immunoregulation and its contribution to tumor-immune escape. Interestingly, blockade of the immunosuppressive activity of galectin-1 within tumor tissue rendered mice resistant to tumor challenge and stimulated the generation of an interferon-g-mediated T helper (TH)1-mediated antitumor response1. These mice were then able to resist subsequent challenge with wild-type Gal-1-sufficient tumors. Investigation of the cellular and molecular mechanisms involved in these effects, revealed that TH1 cells express the repertoire of cell surface glycans that are critical for Gal-1 binding and cell death, whereas TH2 cells are protected from Gal-1 through differential sialylation of N-and O-glycans on cell surface glycoproteins.  Consistently, gal-1 null mutant mice develop hyper-TH1 responses following specific antigenic challenge in vivo and administration of Gal-1 in vivo results in selective elimination of antigen-activated T cells and a T-helper (TH)1 to TH2 shift associated with remission of inflammatory disease. CONCLUSIONS: Our data indicate that Gal-1 signaling in activated T cells constitutes an important mechanism of tumor-immune escape and that blockade of this inhibitory signal can allow for and potentiate effective antitumor immune responses. In addition, our findings identify a novel mechanism, based on differential glycosylation of TH1 and TH2 cells, by which galectin-1 preferentially eliminates antigen-specific TH1 effector cells. PERSPECTIVES AND FUTURE DIRECTIONS: Understanding the paradigms by which protein-sugar interactions regulate tumor-immune escape and inflammation might contribute to the design of rational immunotherapy strategies.