Abstract 1263: Regulation of tumor-specific CD8 T cells via interactions between galectin-3 and surface glycoproteins.

Abstract

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. Abrogation of galectin-3 expression by genetic knock-out in the high avidity CD8 T cells resulted in increased IFN-γ production when compared to wild type controls. Furthermore, 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. Using a combination of microarray and co-immunoprecipitation experiments, we have identified several new binding partners through which galectin-3 may mediate its immunosuppressive functions. 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, Melissa Bowman, Lanqing Huang, Todd Armstrong, Elizabeth Jaffee. Regulation of tumor-specific CD8 T cells via interactions between galectin-3 and surface glycoproteins. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1263. doi:10.1158/1538-7445.AM2013-1263