The Sweet Escape: The Impact of Protein-Glycan Interactions in Tumor Cell Evasion of Immune Responses

G.A. RABINOVICH

ORLANDO (FL)

Conferencia; AMERICAN ASSOCIATION OF HEMATOLOGISTS 2006; 2006

AMERICAN ASSOCIATION OF HEMATOLOGISTS

Scientific Commitee on Lymphocyte Biology Gabriel Rabinovich, Ph.D., Division of Immunogenetics, School of Medicine, University of Buenos Aires, Buenos Aires, Argentina The Sweet Escape: The Impact of Protein-Glycan Interactions in Tumor Cell Evasion of Immune Responses 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 co-operate 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 recently demonstrated that galectin-1, a member of a family of highly conserved sugar-binding proteins, plays a pivotal role in promoting escape from T cell-dependent immunity, thus conferring immune privilege to tumor cells. Galectin-1 is expressed by many different tumor types and its expression correlates with the aggressiveness of these tumors and the acquisition of metastatic phenotypes. In addition, blockade of the immunosuppressive activity of galectin-1 in the tumor microenvironment resulted in reduced tumor mass and enhanced tumor rejection, stimulating the generation of a potent tumor-specific T-cell mediated responses in syngeneic mice. Investigation of the cellular targets and molecular mechanisms involved in this novel immune escape strategy revealed that T helper (TH)1- and TH2-promoting stimuli can differentially regulate the glycosylation pattern of human and murine T-helper cells and modulate their susceptibility to galectin-1. While TH1-differentiated cells express the repertoire of cell surface glycans that are critical for galectin-1 binding and cell death, TH2 cells are protected from galectin-1 through differential sialylation of cell surface glycoproteins.  Understanding the paradigms by which protein-sugar interactions regulate tumor-immune escape and inflammation might contribute to the design of rational antitumor strategies. References 1.Smyth MJ, Dunn GP, Schreiber RD. Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity. Adv. Immunol 2006; 90:1-50. 2.Liu FT, Rabinovich GA. Galectins as modulators of tumor progression. Nature Rev. Cancer 2005; 5:29-41. 3.Rubinstein N, Alvarez M, Zwirner NW, Toscano MA, Ilarregui JM, Bravo A, Mordoh J, Fainboim L, Podhajcer OL, Rabinovich GA. Targeted inhibition of galectin-1 gene expression in tumor cells results in heightened T cell-mediated rejection: A potential mechanism of tumor-immune