Over four decades ago, specific tumor characteristics were ascribed to the increased expression of sialic acid sugars on the surface of cancer cells, and this led to the definition of sialic acids as potential therapeutic targets. Recent advances in glycobiology and cancer research have defined the key processes underlying aberrant expression of sialic acids in cancer, and its consequences, more precisely. These consequences include effects on tumor growth, escape from apoptosis, metastasis formation, and resistance to therapy. Collectively, these novel insights provide further rationale for the design and development of therapeutic approaches that interfere with excessively high expression of sialic acids in cancer cells. Strategies to target aberrant sialylation in cancer, however, have evolved comparatively slowly. Here, we review recent findings that emphasize the detrimental effects of hypersialylation on multiple aspects of tumor growth and behavior. We also discuss novel therapeutic strategies. Cancer Res; 74(12); 3199-204. Ó2014 AACR.

Highlights d Human glycosyltransferases (170 GTf genes) organized in glycosylation pathway maps d The human glycome displayed in a natural context on the cell surface d Sustainable cell-based array resource to dissect biological functions of glycans d Microbial adhesins may bind to clustered patches of Oglycans

Sialic acid sugars on the surface of cancer cells have emerged as potent immune modulators that contribute to the immunosuppressive microenvironment and tumor immune evasion. However, the mechanisms by which these sugars modulate antitumor immunity as well as therapeutic strategies directed against them are limited. Here we report that intratumoral injections with a sialic acid mimetic Ac3FNeu5Ac block tumor sialic acid expression and suppress tumor growth in multiple tumor models. Sialic acid blockade had a major impact on the immune cell composition of the tumor, enhancing tumor-infiltrating natural killer cell and CD8 T-cell numbers while reducing regulatory T-cell and myeloid regulatory cell numbers. Sialic acid blockade enhanced cytotoxic CD8 T-cell-mediated killing of tumor cells in part by facilitating antigen-specific T-cell-tumor cell clustering. Sialic acid blockade also synergized with adoptive transfer of tumor-specific CD8 T cells and enhanced CpG immune adjuvant therapy by increasing dendritic cell activation and subsequent CD8 T-cell responses. Collectively, these data emphasize the crucial role of sialic acids in tumor immune evasion and provide proof of concept that sialic acid blockade creates an immune-permissive tumor microenvironment for CD8 T-cell-mediated tumor immunity, either as single treatment or in combination with other immune-based intervention strategies. Sialic acid sugars function as important modulators of the immunosuppressive tumor microenvironment that limit potent antitumor immunity. http://cancerres.aacrjournals.org/content/canres/78/13/3574/F1.large.jpg .

Cancer cells decorate their surface with a dense layer of sialylated glycans by upregulating the expression of sialyltransferases and other glycogenes. Although sialic acids play a vital role in many biologic processes, hypersialylation in particular has been shown to contribute to cancer cell progression and metastasis. Accordingly, selective strategies to interfere with sialic acid synthesis might offer a powerful approach in cancer therapy. In the present study, we assessed the potential of a recently developed fluorinated sialic acid analogue (P-3F ax -Neu5Ac) to block the synthesis of sialoglycans in murine melanoma cells and the consequences on cell adhesion, migration, and in vivo growth. The results showed that P-3F ax -Neu5Ac readily caused depletion of a2,3-/a2,6-linked sialic acids in B16F10 cells for several days. Long-term inhibition of sialylation for 28 days was feasible without affecting cell viability or proliferation. Moreover, P-3F ax -Neu5Ac proved to be a highly potent inhibitor of sialylation even at high concentrations of competing sialyltransferase substrates. P-3F ax -Neu5Ac-treated cancer cells exhibited impaired binding to poly-L-lysine, type I collagen, and fibronectin and diminished migratory capacity. Finally, blocking sialylation of B16F10 tumor cells with this novel sialic acid analogue reduced their growth in vivo. These results indicate that P-3F ax -Neu5Ac is a powerful glycomimetic capable of inhibiting aberrant sialylation that can potentially be used for anticancer therapy. Mol Cancer Ther; 12(10); 1935-46. Ó2013 AACR.

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Mucins are a large family of heavily O-glycosylated proteins that cover all mucosal surfaces and constitute the major macromolecules in most body fluids. Mucins are primarily defined by their variable tandem repeat (TR) domains that are densely decorated with different O-glycan structures in distinct patterns, and these arguably convey much of the informational content of mucins. Here, we develop a cell-based platform for the display and production of human TR O-glycodomains (~200 amino acids) with tunable structures and patterns of O-glycans using membrane-bound and secreted reporters expressed in glycoengineered HEK293 cells. Availability of defined mucin TR O-glycodomains advances experimental studies into the versatile role of mucins at the interface with pathogenic microorganisms and the microbiome, and sparks new strategies for molecular dissection of specific roles of adhesins, glycoside hydrolases, glycopeptidases, viruses and other interactions with mucin TRs as highlighted by examples.

Saponin-based adjuvants (SBAs) are being used in animal and human (cancer) vaccines, as they induce protective cellular immunity. Their adjuvant potency is a factor of inflammasome activation and enhanced antigen cross-presentation by dendritic cells (DCs), but how antigen cross-presentation is induced is not clear. Here we show that SBAs uniquely induce intracellular lipid bodies (LBs) in the CD11b+ DC subset in vitro and in vivo. Using genetic and pharmacological interference in models for vaccination and in situ tumour ablation, we demonstrate that LB induction is causally related to the saponin-dependent increase in cross-presentation and T-cell activation. These findings link adjuvant activity to LB formation, aid the application of SBAs as a cancer vaccine component, and will stimulate development of new adjuvants enhancing T-cell-mediated immunity.