Tumor desialylation surpasses anti‐ PD ‐ L1 checkpoint therapy in restoring anti‐tumor immunity in a murine model for colorectal cancer

作者：Irene van der Haar Àvila, Tao Zhang, Victor Lorrain, Eelco D. Keuning, Laraib Amir Ali, Cora H. Chadick, Sara García‐García, Louis Boon, Noortje de Haan, Juan Jesús García-Vallejo, Yvette van Kooyk, Sandra J. van Vliet · 发表于：International Journal of Cancer · 年份：2025 · DOI：10.1002/ijc.70031 · 被引用次数：7 · 研究领域：Glycosylation and Glycoproteins Research、Immune Cell Function and Interaction、Cancer Immunotherapy and Biomarkers

Abnormal levels of tumor-associated glycans are correlated with tumor progression in many types of cancer, including (CRC). Sialic acids, a family of nine-carbon monosaccharides, are key regulators of the anti-tumor immune response via Siglecs, yet the sialic acid-specific effects are highly dependent on the tumor type studied. Therefore, a detailed understanding of sialic acid-mediated immunomodulation in different tumor contexts is warranted. Using CRISPR/Cas9 technology, we generated an isogenic knockout of the N-acylneuraminate cytidylyltransferase (Cmas) gene in CT26 CRC cells, thus creating cells that lack cell surface sialylation. Compared to CT26-MOCK control cells, CT26-CMAS KO cells displayed significantly reduced tumor growth in vivo, resulting in increased survival of the mice. This difference was absent in immunodeficient mice, signifying an immune-dependent effect. High-dimensional profiling of immune cell networks in the tumor microenvironment revealed increased infiltration and differentiation trajectories of lymphoid cells in the CT26-CMAS KO tumors, especially of natural killer (NK) cells and γδ T cells. Strikingly, sialic acid ablation resulted in a stronger immunostimulatory capacity and did not synergize with anti-PD-L1 checkpoint inhibition, suggesting that at least in the CT26 model, sialic acids impose a superior immune inhibitory circuit than the well-known PD-1/PD-L1 pathway. Overall, our findings strengthen the concept of sialic acid-mediated impair...