Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment

Hannah Egan; Oliver Treacy; Kevin Lynch; Niamh A Leonard; Grace O'Malley; Eileen Reidy; Aoise O'Neill; Shania M Corry; Kim De Veirman; Karin Vanderkerken; Laurence J Egan; Thomas Ritter; Aisling M Hogan; Keara Redmond; Li Peng; Jenny Che; Wayne Gatlin; Pushpa Jayaraman; Margaret Sheehan; Aoife Canney; Sean O Hynes; Emma M Kerr; Philip D Dunne; Michael E O'Dwyer; Aideen E Ryan

doi:10.1016/j.celrep.2023.112475

Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment

Hannah Egan, Oliver Treacy, Kevin Lynch, Niamh A Leonard, Grace O'Malley, Eileen Reidy, Aoise O'Neill, Shania M Corry, Kim De Veirman, Karin Vanderkerken, Laurence J Egan, Thomas Ritter, Aisling M Hogan, Keara Redmond, Li Peng, Jenny Che, Wayne Gatlin, Pushpa Jayaraman, Margaret Sheehan, Aoife CanneySean O Hynes, Emma M Kerr, Philip D Dunne, Michael E O'Dwyer, Aideen E Ryan

Patrick G Johnston Centre for Cancer Research

Research output: Contribution to journal › Article › peer-review

23 Citations (Scopus)

Abstract

Immunosuppressive tumor microenvironments (TMEs) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells, which results in inhibition of effector functions. The role of sialylation in shaping MSC/CAF immunosuppression in the TME is not well characterized. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid, and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory CD8 PD1 and CD8 Siglec-7 /Siglec-9 T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as shown by infiltration of CD25 and granzyme B-expressing CD8 T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME.

Original language	English
Article number	112475
Number of pages	26
Journal	Cell Reports
Early online date	10 May 2023
DOIs	https://doi.org/10.1016/j.celrep.2023.112475
Publication status	Early online date - 10 May 2023

Keywords

CP: Immunology
T cells
cancer-associated fibroblasts
immunotherapy
T cell exhaustion
stromal cells
CP: Cancer
inflammation
sialylation
colon cancer
siglecs
tumor microenvironment

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2023.112475Licence: CC BY

Molecular evolution of aggressive early stage colorectal cancer
Corry, S. M. (Author), Lawler, M. (Supervisor) & Dunne, P. (Supervisor), Jul 2024
Student thesis: Doctoral Thesis › Doctor of Philosophy

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Egan, H., Treacy, O., Lynch, K., Leonard, N. A., O'Malley, G., Reidy, E., O'Neill, A., Corry, S. M., De Veirman, K., Vanderkerken, K., Egan, L. J., Ritter, T., Hogan, A. M., Redmond, K., Peng, L., Che, J., Gatlin, W., Jayaraman, P., Sheehan, M., ... Ryan, A. E. (2023). Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment. Cell Reports, Article 112475. Advance online publication. https://doi.org/10.1016/j.celrep.2023.112475

@article{607d6975a64241bc841bc720c1599258,

title = "Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment",

abstract = "Immunosuppressive tumor microenvironments (TMEs) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells, which results in inhibition of effector functions. The role of sialylation in shaping MSC/CAF immunosuppression in the TME is not well characterized. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid, and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory CD8 PD1 and CD8 Siglec-7 /Siglec-9 T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as shown by infiltration of CD25 and granzyme B-expressing CD8 T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME. ",

keywords = "CP: Immunology, T cells, cancer-associated fibroblasts, immunotherapy, T cell exhaustion, stromal cells, CP: Cancer, inflammation, sialylation, colon cancer, siglecs, tumor microenvironment",

author = "Hannah Egan and Oliver Treacy and Kevin Lynch and Leonard, {Niamh A} and Grace O'Malley and Eileen Reidy and Aoise O'Neill and Corry, {Shania M} and {De Veirman}, Kim and Karin Vanderkerken and Egan, {Laurence J} and Thomas Ritter and Hogan, {Aisling M} and Keara Redmond and Li Peng and Jenny Che and Wayne Gatlin and Pushpa Jayaraman and Margaret Sheehan and Aoife Canney and Hynes, {Sean O} and Kerr, {Emma M} and Dunne, {Philip D} and O'Dwyer, {Michael E} and Ryan, {Aideen E}",

year = "2023",

month = may,

day = "10",

doi = "10.1016/j.celrep.2023.112475",

language = "English",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

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Egan, H, Treacy, O, Lynch, K, Leonard, NA, O'Malley, G, Reidy, E, O'Neill, A, Corry, SM, De Veirman, K, Vanderkerken, K, Egan, LJ, Ritter, T, Hogan, AM, Redmond, K, Peng, L, Che, J, Gatlin, W, Jayaraman, P, Sheehan, M, Canney, A, Hynes, SO, Kerr, EM , Dunne, PD, O'Dwyer, ME & Ryan, AE 2023, 'Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment', Cell Reports. https://doi.org/10.1016/j.celrep.2023.112475

TY - JOUR

T1 - Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment

AU - Egan, Hannah

AU - Treacy, Oliver

AU - Lynch, Kevin

AU - Leonard, Niamh A

AU - O'Malley, Grace

AU - Reidy, Eileen

AU - O'Neill, Aoise

AU - Corry, Shania M

AU - De Veirman, Kim

AU - Vanderkerken, Karin

AU - Egan, Laurence J

AU - Ritter, Thomas

AU - Hogan, Aisling M

AU - Redmond, Keara

AU - Peng, Li

AU - Che, Jenny

AU - Gatlin, Wayne

AU - Jayaraman, Pushpa

AU - Sheehan, Margaret

AU - Canney, Aoife

AU - Hynes, Sean O

AU - Kerr, Emma M

AU - Dunne, Philip D

AU - O'Dwyer, Michael E

AU - Ryan, Aideen E

PY - 2023/5/10

Y1 - 2023/5/10

N2 - Immunosuppressive tumor microenvironments (TMEs) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells, which results in inhibition of effector functions. The role of sialylation in shaping MSC/CAF immunosuppression in the TME is not well characterized. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid, and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory CD8 PD1 and CD8 Siglec-7 /Siglec-9 T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as shown by infiltration of CD25 and granzyme B-expressing CD8 T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME.

AB - Immunosuppressive tumor microenvironments (TMEs) reduce the effectiveness of immune responses in cancer. Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote tumor progression by enhancing immune cell suppression in colorectal cancer (CRC). Hyper-sialylation of glycans promotes immune evasion in cancer through binding of sialic acids to their receptors, Siglecs, expressed on immune cells, which results in inhibition of effector functions. The role of sialylation in shaping MSC/CAF immunosuppression in the TME is not well characterized. In this study, we show that tumor-conditioned stromal cells have increased sialyltransferase expression, α2,3/6-linked sialic acid, and Siglec ligands. Tumor-conditioned stromal cells and CAFs induce exhausted immunomodulatory CD8 PD1 and CD8 Siglec-7 /Siglec-9 T cell phenotypes. In vivo, targeting stromal cell sialylation reverses stromal cell-mediated immunosuppression, as shown by infiltration of CD25 and granzyme B-expressing CD8 T cells in the tumor and draining lymph node. Targeting stromal cell sialylation may overcome immunosuppression in the CRC TME.

KW - CP: Immunology

KW - T cells

KW - cancer-associated fibroblasts

KW - immunotherapy

KW - T cell exhaustion

KW - stromal cells

KW - CP: Cancer

KW - inflammation

KW - sialylation

KW - colon cancer

KW - siglecs

KW - tumor microenvironment

U2 - 10.1016/j.celrep.2023.112475

DO - 10.1016/j.celrep.2023.112475

M3 - Article

C2 - 37167967

SN - 2211-1247

JO - Cell Reports

JF - Cell Reports

M1 - 112475

ER -

Targeting stromal cell sialylation reverses T cell-mediated immunosuppression in the tumor microenvironment

Abstract

Keywords

UN SDGs

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Student theses

Molecular evolution of aggressive early stage colorectal cancer

Cite this