Unlocking bowel cancer immunity: Scientists strip complex sugar cloak defense

Good news! Cancer is history (soon)!

"In a world-first breakthrough, scientists have discovered how a sugary “cloak” helps bowel cancer hide from the immune system, and how stripping it away could turn the body’s anti-cancer defenses back on. ...

In a new study ... researchers have looked at why some bowel cancers can evade the immune system and resist treatments like immunotherapy, and found that a kind of “sugar coating” on stromal cells within a tumor plays a key role in shutting down immune attack. Importantly, they found that removing or blocking this coating reawakened immune defenses. ..."

"... The breakthrough research discovery is the first to demonstrate that tumour stromal cells – the structural cells that support cancer growth – are directly reprogramming the immune system. They do this by switching off, or hijacking, two of our body’s most important tumour-fighting cells – the natural killers (NK) and macrophages – rendering them unable to attack the cancer. ..."

From the abstract (this abstract is loaded with terminology, which is regrettable):

"Background

The immunosuppressive tumor microenvironment reduces immune response effectiveness in stromal-rich tumors, including consensus molecular subtype 4 colorectal cancer (CRC). Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote cancer progression by suppressing anti-tumor immune responses. Hypersialylation of glycans on tumors engages Siglec receptors on immune cells, driving immune dysfunction, but its role in stromal-mediated suppression of innate immunity remains unclear.

Methods

Sialylation, Sialic acids and Siglec ligands were measured on CRC tissue, primary human normal-associated fibroblasts (NAFs), CAFs, and tumor-conditioned MSCs (MSCTCS) using transcriptional profiles, immunohistochemistry and flow cytometry, respectively. The effect of stromal cell sialylation on macrophages and NK cells was assessed in ex vivo human primary stromal and immune cell co-cultures, and expression of Siglec-10 and immune cell phenotype markers and function was measured by flow cytometry and real-time imaging. Using an immunocompetent Balb/c CT26 mouse model, we induced tumors with/without conditioned stromal cells, with/without pretreatment of stromal cells with sialyltransferase inhibitor (3FAX) or sialidase (E610). We assessed the effect of stromal cell sialylation on macrophages and NK cells in the tumor and secondary lymphoid tissues by flow cytometry.

Results

Stromal cells, including CAFs, in CRC tumors are highly sialylated compared with epithelial cancer cells and are associated with high expression of the sialyltransferase ST6GALNAC6.

Genetic knockdown of ST6GALNAC6 reduced the expression of stromal cell Siglec-10 ligands in MSCs. CAFs and MSCTCS induced Siglec-10 on macrophages and NK cells and impaired macrophage phagocytosis and NK cell cytotoxicity.

Sialidase treatment reduced Siglec-10 expression, restoring macrophage and NK cell antitumor functions. In vivo and ex vivo, desialylation of stromal cells increased macrophage activation (CD11b+CD80+) and reduced immunosuppressive marker expression (CD206, PD-L1, Siglec-G) in lymphoid tissues, indicating sustained systemic anti-tumor immunity.

Intratumoral NK cells exhibited high Siglec-G expression and impaired cytotoxicity, and granzyme B expression significantly increased with sialidase treatment of stromal cells.

In an inflammatory tumor model, inflammatory tumor-conditioned MSCs (MSCiTCS) promoted metastasis and Siglec-G induction on NK cells and macrophages, both reversed by sialyltransferase inhibition, underscoring the effects of stromal modulation of innate immune cell function in inflammatory tumors.

Conclusions

Stromal cell sialylation modulates innate immune suppression in CRC via the sialic acid/Siglec axis. Targeting stromal sialylation restores NK cytotoxicity and macrophage activation, offering novel insights that may shape therapeutic strategies for reversing immunosuppression in stromal-rich tumors."

Unlocking bowel cancer immunity: Scientists strip sugar cloak defense

Research shows world-first breakthrough for bowel cancer immunotherapy

Stromal cells modulate innate immune cell phenotype and function in colorectal cancer via the Sialic acid/Siglec axis (open access)

Why do cancer researchers in Ireland dress like cooks? Is it because of bowel cancer? Caution: irony.

Fig. 1 Sialylation is upregulated in CMS4 colorectal cancer.

Fig. 8 Targeting sialylation of stroma in inflammatory in vivo models of CRC reduces Siglec-G expression in tumor-infiltrating macrophages and NK cells.