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

Lenneke A M Cornelissen, Athanasios Blanas, Joost C van der Horst, Laura Kruijssen, Anouk Zaal, Tom O'Toole, Lieke Wiercx, Yvette van Kooyk, Sandra J van Vliet

Research output: Contribution to journalArticleAcademicpeer-review

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 CIRSPR/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. This article is protected by copyright. All rights reserved.

LanguageEnglish
JournalInternational Journal of Cancer
DOIs
Publication statusE-pub ahead of print - 22 Dec 2018

Cite this

@article{5e0a6d43039d40c5a44e7e7003a01918,
title = "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 CIRSPR/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. This article is protected by copyright. All rights reserved.",
author = "Cornelissen, {Lenneke A M} and Athanasios Blanas and {van der Horst}, {Joost C} and Laura Kruijssen and Anouk Zaal and Tom O'Toole and Lieke Wiercx and {van Kooyk}, Yvette and {van Vliet}, {Sandra J}",
note = "This article is protected by copyright. All rights reserved.",
year = "2018",
month = "12",
day = "22",
doi = "10.1002/ijc.32084",
language = "English",
journal = "International Journal of Cancer",
issn = "0020-7136",
publisher = "Wiley-Liss Inc.",

}

Disruption of sialic acid metabolism drives tumor growth by augmenting CD8+ T cell apoptosis. / Cornelissen, Lenneke A M; Blanas, Athanasios; van der Horst, Joost C; Kruijssen, Laura; Zaal, Anouk; O'Toole, Tom; Wiercx, Lieke; van Kooyk, Yvette; van Vliet, Sandra J.

In: International Journal of Cancer, 22.12.2018.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Disruption of sialic acid metabolism drives tumor growth by augmenting CD8+ T cell apoptosis

AU - Cornelissen, Lenneke A M

AU - Blanas, Athanasios

AU - van der Horst, Joost C

AU - Kruijssen, Laura

AU - Zaal, Anouk

AU - O'Toole, Tom

AU - Wiercx, Lieke

AU - van Kooyk, Yvette

AU - van Vliet, Sandra J

N1 - This article is protected by copyright. All rights reserved.

PY - 2018/12/22

Y1 - 2018/12/22

N2 - 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 CIRSPR/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. This article is protected by copyright. All rights reserved.

AB - 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 CIRSPR/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. This article is protected by copyright. All rights reserved.

U2 - 10.1002/ijc.32084

DO - 10.1002/ijc.32084

M3 - Article

JO - International Journal of Cancer

T2 - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

ER -