Disruption of sialic acid metabolism drives tumor growth by augmenting CD8⁺ T cell apoptosis

Abstract

Sialylated glycan structures are known for their immunomodulatory capacities and their contribution to tumor immune evasion. However, the role of aberrant sialylation in colorectal cancer and the consequences of complete tumor desialylation on anti‐tumor immunity remain unstudied. Here, we report that CRISPR/Cas9‐mediated knock out of the CMAS gene, encoding a key enzyme in the sialylation pathway, in the mouse colorectal cancer MC38 cell line completely abrogated cell surface expression of sialic acids (MC38‐Sianull) and, unexpectedly, significantly increased in vivo tumor growth compared to the control MC38‐MOCK cells. This enhanced tumor growth of MC38‐Sianull cells could be attributed to decreased CD8+ T cell frequencies in the tumor microenvironment only, as immune cell frequencies in tumor‐draining lymph nodes remained unaffected. In addition, MC38‐Sianull cells were able to induce CD8+ T cell apoptosis in an antigen‐independent manner. Moreover, low CMAS gene expression correlated with reduced recurrence‐free survival in a human colorectal cancer cohort, supporting the clinical relevance of our work. Together, these results demonstrate for the first time a detrimental effect of complete tumor desialylation on colorectal cancer tumor growth, which greatly impacts the design of novel cancer therapeutics aimed at altering the tumor glycosylation profile.

Tn Antigen Expression Contributes to an Immune Suppressive Microenvironment and Drives Tumor Growth in Colorectal Cancer

“…We first explored the impact of high Tn antigen expression on tumor growth through subcutaneous injection of the MC38-MOCK and MC38-Tn high cell lines in C57Bl/6 mice. Interestingly, and in contrast to a sialic acid knockout of MC38 ( 37 ), the in vivo growth rates were similar between MC38-MOCK and MC38-Tn high tumors at day 13 of tumor development ( Figures 3A,B ). However, from day 23 onward MC38-Tn high tumors started to display significantly faster growth compared to the MC38-MOCK tumors ( Figures 3C,D ).…”

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

“…CD24 on tumor cells interacts with siglec-10 on tumor-associated macrophages to promote immune evasion [48]. Blocking siglec-15 or siglec-9 disinhibited T cell activities and reduced tumor growth [49][50][51]. Focusing the immune inhibitory function of sialic acids and targeting sialic acid receptors offer potential important immunotherapy in cancer [52].…”

The Roles of Siglec7 and Siglec9 on Natural Killer Cells in Virus Infection and Tumour Progression

“…Natural killer (NK) cells are essential innate immune cells which are able to directly kill unhealthy host cells, including virus-infected cells [1] and tumour cells [2]. Due to the downregulation of MHC I of virus-infected cells and tumour cells, the target cells can escape from the specific recognition of T cells [3]. However, NK cell-mediated cytotoxicity does not require antigenic stimulation and is not restricted by MHC I molecules.…”