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Disruption of sialic acid metabolism drives tumor growth by augmenting CD8 + T cell apoptosis
Author(s) -
Cornelissen Lenneke A.M.,
Blanas Athanasios,
Horst Joost C.,
Kruijssen Laura,
Zaal Anouk,
O'Toole Tom,
Wiercx Lieke,
Kooyk Yvette,
Vliet Sandra J.
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32084
Subject(s) - cancer research , cd8 , cancer , biology , colorectal cancer , immune system , tumor microenvironment , sialic acid , apoptosis , cancer cell , cell growth , t cell , cell , cytotoxic t cell , immunology , biochemistry , in vitro , genetics
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‐Sia null ) and, unexpectedly, significantly increased in vivo tumor growth compared to the control MC38‐MOCK cells. This enhanced tumor growth of MC38‐Sia null 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‐Sia null 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.