Shifting immune cells toward cancer-fighting mode: Sugar-coated extensions reveal a potential target

Macrophages, immune cells found within our bodies, typically combat bacteria and cancer cells. However, when these cells infiltrate tumors, they can transform into tumor-associated macrophages (TAMs), which adopt an immunosuppressive, anti-inflammatory role. This shift is detrimental as it prevents the immune system from effectively combating tumors. Patients suffering from colorectal cancer with elevated levels of anti-inflammatory TAMs often experience a more adverse prognosis.

Nagoya University in Japan and their international collaborators discovered that the sialic acid sugar structures on the macrophage surface undergo significant alterations during this transformation from a pro-inflammatory to an anti-inflammatory state. The enzyme ST6GAL1 emerges as a primary catalyst for this change. By inhibiting ST6GAL1 in tumor-promoting macrophages, growth of colorectal cancer cells was significantly diminished in laboratory settings.

Macrophages are enveloped by a glycocalyx, a layer of proteins, lipids, and sugar chains facilitating cell-to-cell communication. These chains, capped with sialic acid, manifest primarily in two linkage types: α2,3 and α2,6. While altered sialylation assists cancer cells in evading immune detection, the changes in these sugars as macrophages polarize remain enigmatic.

To elucidate this, a team led by assistant professor Priya Dipta from Nagoya University Institute for Glyco-Core Research and professor Morten Thaysen-Andersen from Macquarie University in Australia, in collaboration with researchers from Nagoya University Graduate School of Medicine, conducted an investigation. They isolated monocytes from healthy donors and differentiated them into tumor-fighting and tumor-promoting macrophages, examining glycan linkages via mass spectrometry and glycan-specific protein staining.

They observed that tumor-fighting macrophages demonstrated a higher presence of α2,3-linked sialic acids on N-glycans on the cell surface, whereas nearly 90% of the sialic acids in tumor-promoting macrophages were α2,6-linked. Fluorescence microscopy revealed elongated, branching extensions, termed sialo-protrusions, coated with α2,6-linked sialic acids, extending up to 800 micrometers from tumor-promoting macrophages to form a mesh-like network connecting nearby cells. Conversely, tumor-fighting macrophages exhibited fewer of these protrusions.

These protrusions lacked evidence of actin, a protein typically involved in cellular extensions, instead showcasing α2,6-sialylated glycoproteins on their surface, indicating a distinct nature from previously reported actin-based protrusions. Importantly, only tumor-promoting macrophages produce high levels of ST6GAL1. Suppressing this enzyme with siRNA resulted in the fragmentation and shortening of sialo-protrusions, decreased cell movement, reduced cell-to-cell interaction, and diminished contact with colorectal cancer cells.

Furthermore, cancer cell growth slowed substantially, implying that sialo-protrusions aid macrophages in movement, communication with cancer cells, and contribute to tumor growth via such connections. When ST6GAL1 was inhibited, tumor-promoting macrophages began to resemble tumor-fighting macrophages in terms of shape, cytokine expression, and phagocytic ability, suggesting that targeting this single enzyme can substantially alter macrophage states.

The team observed a similar pattern of sialic acid linkages in patient-derived colorectal cancer tissue, with more α2,6 sialic acid on tumor-promoting TAMs and more α2,3 sialic acid on tumor-fighting TAMs. Dipta remarked, "These findings offer a novel perspective on how remodeling of the immune cell glycocalyx may impact the tumor microenvironment."

Future research should explore ST6GAL1 inhibition in vivo to assess its potential as an antitumor therapy. Additionally, researchers aim to identify the proteins constituting the sialo-protrusions and understand how these structures mediate communication, paving the way for new cancer immunotherapy strategies.