Hypersialylation in Cancer: Modulation of Inflammation and Therapeutic Opportunities

Abstract

Cell surface glycosylation is dynamic and often changes in response to cellular differentiation under physiological or pathophysiological conditions. Altered glycosylation on cancers cells is gaining attention due its wide-spread occurrence across a variety of cancer types and recent studies that have documented functional roles for aberrant glycosylation in driving cancer progression at various stages. One change in glycosylation that can correlate with cancer stage and disease prognosis is hypersialylation. Increased levels of sialic acid are pervasive in cancer and a growing body of evidence demonstrates how hypersialylation is advantageous to cancer cells, particularly from the perspective of modulating immune cell responses. Sialic acid-binding receptors, such as Siglecs and Selectins, are well-positioned to be exploited by cancer hypersialylation. Evidence is also mounting that Siglecs modulate key immune cell types in the tumor microenvironment, particularly those responsible for maintaining the appropriate inflammatory environment. From these studies have come new and innovative ways to block the effects of hypersialylation by directly reducing sialic acid on cancer cells or blocking interactions between sialic acid and Siglecs or Selectins. Here we review recent works examining how cancer cells become hypersialylated, how hypersialylation benefits cancer cells and tumors, and proposed therapies to abrogate hypersialylation of cancer.

Keywords: Selectin; Siglec; glycosylation; immunosurveillance; inflammation; lectin; sialic acid; tumor-associated macrophage.

Figure 1

Hypersialylation in cancer: causes and effects. Elevated levels of sialic acid on transformed cells can be driven by at least three different mechanisms. Hypersialylation on cancer cells can promote tumor development and survival in a many of different ways but one key mechanism is through modulating immune cell responses and in particular those immune cells types involved in modulating the inflammatory environment in tumors.

Figure 2

Roles for hypersialylation on cancer in modulating Siglecs on immune cells. (a) Siglec-7 (and potentially Siglec-9) on NK cells can be drawn into an immunological synapse formed with a cancer cell to inhibit an activatory receptor (e.g., CD16), thereby inhibiting NK cell-mediated killing; (b) Siglec-9 on neutrophils can be engaged by hypersialylation of cancer cells and prevent neutrophil-mediated killing of cancer cells through an unknown activatory receptor and ligand on the cancer cells; (c) Siglec-9 on macrophages can promote or inhibit skewing of macrophages to a tumor-associated or tumor-promoting phenotype through engagement of sialic acid-containing glycans on cancer cells; (d) Siglec-15 on macrophages pairs with the adapter protein Dap12 to activate cellular signaling in response to sialic acid ligands on cancer cells, thereby inducing TGF-β production; (e) CD33 (Siglec-3) on myeloid-derived suppressor cells (MDSCs) has been shown to modulate inflammatory responses through modulating TLR4.

Figure 3

Therapeutic strategies for modulating sialic acid expression and interactions between sialic acid and sialic acid-binding receptors. (Upper left portion of cell): delivery of 3F-Neu5Ac to cancer cells to decrease sialic acid expression. 3F-Neu5Ac is typically delivered in its peracetylated form to penetrate the cell membrane. Once inside the cell, 3F-Neu5Ac is converted into CMP-3F-Neu5Ac and blocks the actions of STs in the secretory pathway. (Upper right portion of cell): blocking antibodies that abrogate the interaction between sialic acid on cancer cells and sialic acid-binding receptors on immune cells, such as Siglecs, have the potential of being a new class of immune checkpoint inhibitor. (Lower portion of the cell): antibody directed to the tumor, such as anti-HER2 to target breast cancer cells, have been conjugated to neuraminidase to cleave the sialic acid residues on the cancer cells.