Abstract B59: Regulation of tumor-specific CD8 T cells via interactions between galectin-3 and surface glycoproteins. (2013)

Abstract This study is testing the hypothesis that galectin-3, a 31 KDa carbohydrate-binding lectin, is involved in regulating T cell function within the tumor micro-environment by interacting with oligosaccharide chains on cell surface glycoproteins. Our interest in galectin-3 arose when we found that patients responding to a granulocyte-macrophage colony-stimulating factor (GM-CSF) secreting allogeneic pancreatic tumor vaccine developed post immunization antibody responses to galectin-3 on a proteomic screen. Oligosaccharide chains on plasma membrane proteins form a thick coat known as the glycocalyx that surrounds the entire cell. The glycocalyx has been shown to be important in regulating a diverse array of cellular processes such as adhesion, growth, and trafficking via its interactions with ligands on neighboring cells or in the extracellular environment. Lectin mediated clustering of receptors can lead to activation of downstream signaling proteins or even impact the half-life of a receptor on the cell-surface, thus affecting the duration of signaling. Changes in oligosaccharide structure through differential expression of enzymes involved in the glycosylation pathway may therefore modulate cellular activity by altering the availability and structure of binding motifs for glycan-binding proteins. Thus, the importance of lectin-glycan interactions in tumor development and the corresponding anti-tumor immune response cannot be ignored. Galectin-3 is over-expressed in several different malignancies. It has also been shown to modulate T cell responses through a diverse array of mechanisms including induction of apoptosis, TCR cross linking in CD8+ T cells, and T cell receptor (TCR) down regulation in CD4+ T cells. We have used the HER-2/neu (neu-N) transgenic mouse model to study galectin-3 binding on adoptively transferred high avidity neu-specific CD8+ T cells derived from TCR transgenic mice. Galectin-3 binding was found to be associated with increased expression of programmed death 1 (PD1) and apoptosis markers in vivo, and diminished cytokine production in vitro. We also observed that galectin-3 binding to the T cell surface occurs in an autocrine manner, and is dependant on antigen stimulation as well as sialylation of terminal galactose residues. Microarray analyses of galectin-3 bound CD8+ tumor infiltrating lymphocytes (TILs) have identified CEACAM1 (CD66) and TIM-3 as possible targets through which galectin-3 can inhibit T cell function. These studies provide a potential new mechanism by which the function of antigen-specific T cells is down-regulated after trafficking into the tumor micro-environment. Citation Format: Theodore S. Kouo, Lanqing Huang, Todd Armstrong, Elizabeth M. Jaffee. Regulation of tumor-specific CD8 T cells via interactions between galectin-3 and surface glycoproteins. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B59.