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Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology of the disease. Here, we identified galectin 4 (gal 4) as a cancer cell–produced protein that was deposited into the ECM of PDAC tumors and detected high-circulating...

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Autores principales: Lidström, Tommy, Cumming, Joshua, Gaur, Rahul, Frängsmyr, Lars, Pateras, Ioannis S., Mickert, Matthias J., Franklin, Oskar, Forsell, Mattias N.E., Arnberg, Niklas, Dongre, Mitesh, Patthey, Cedric, Öhlund, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9808371/
https://www.ncbi.nlm.nih.gov/pubmed/36478037
http://dx.doi.org/10.1158/2326-6066.CIR-21-1088
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author Lidström, Tommy
Cumming, Joshua
Gaur, Rahul
Frängsmyr, Lars
Pateras, Ioannis S.
Mickert, Matthias J.
Franklin, Oskar
Forsell, Mattias N.E.
Arnberg, Niklas
Dongre, Mitesh
Patthey, Cedric
Öhlund, Daniel
author_facet Lidström, Tommy
Cumming, Joshua
Gaur, Rahul
Frängsmyr, Lars
Pateras, Ioannis S.
Mickert, Matthias J.
Franklin, Oskar
Forsell, Mattias N.E.
Arnberg, Niklas
Dongre, Mitesh
Patthey, Cedric
Öhlund, Daniel
author_sort Lidström, Tommy
collection PubMed
description Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology of the disease. Here, we identified galectin 4 (gal 4) as a cancer cell–produced protein that was deposited into the ECM of PDAC tumors and detected high-circulating levels of gal 4 in patients with PDAC. In orthotopic transplantation experiments, we observed increased infiltration of T cells and prolonged survival in immunocompetent mice transplanted with cancer cells with reduced expression of gal 4. Increased survival was not observed in immunodeficient RAG1(−/−) mice, demonstrating that the effect was mediated by the adaptive immune system. By performing single-cell RNA-sequencing, we found that the myeloid compartment and cancer-associated fibroblast (CAF) subtypes were altered in the transplanted tumors. Reduced gal 4 expression associated with a higher proportion of myofibroblastic CAFs and reduced numbers of inflammatory CAFs. We also found higher proportions of M1 macrophages, T cells, and antigen-presenting dendritic cells in tumors with reduced gal 4 expression. Using a coculture system, we observed that extracellular gal 4 induced apoptosis in T cells by binding N-glycosylation residues on CD3ε/δ. Hence, we show that gal 4 is involved in immune evasion and identify gal 4 as a promising drug target for overcoming immunosuppression in PDAC.
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spelling pubmed-98083712023-01-17 Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer Lidström, Tommy Cumming, Joshua Gaur, Rahul Frängsmyr, Lars Pateras, Ioannis S. Mickert, Matthias J. Franklin, Oskar Forsell, Mattias N.E. Arnberg, Niklas Dongre, Mitesh Patthey, Cedric Öhlund, Daniel Cancer Immunol Res Research Articles Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology of the disease. Here, we identified galectin 4 (gal 4) as a cancer cell–produced protein that was deposited into the ECM of PDAC tumors and detected high-circulating levels of gal 4 in patients with PDAC. In orthotopic transplantation experiments, we observed increased infiltration of T cells and prolonged survival in immunocompetent mice transplanted with cancer cells with reduced expression of gal 4. Increased survival was not observed in immunodeficient RAG1(−/−) mice, demonstrating that the effect was mediated by the adaptive immune system. By performing single-cell RNA-sequencing, we found that the myeloid compartment and cancer-associated fibroblast (CAF) subtypes were altered in the transplanted tumors. Reduced gal 4 expression associated with a higher proportion of myofibroblastic CAFs and reduced numbers of inflammatory CAFs. We also found higher proportions of M1 macrophages, T cells, and antigen-presenting dendritic cells in tumors with reduced gal 4 expression. Using a coculture system, we observed that extracellular gal 4 induced apoptosis in T cells by binding N-glycosylation residues on CD3ε/δ. Hence, we show that gal 4 is involved in immune evasion and identify gal 4 as a promising drug target for overcoming immunosuppression in PDAC. American Association for Cancer Research 2023-01-03 2022-12-20 /pmc/articles/PMC9808371/ /pubmed/36478037 http://dx.doi.org/10.1158/2326-6066.CIR-21-1088 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
spellingShingle Research Articles
Lidström, Tommy
Cumming, Joshua
Gaur, Rahul
Frängsmyr, Lars
Pateras, Ioannis S.
Mickert, Matthias J.
Franklin, Oskar
Forsell, Mattias N.E.
Arnberg, Niklas
Dongre, Mitesh
Patthey, Cedric
Öhlund, Daniel
Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer
title Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer
title_full Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer
title_fullStr Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer
title_full_unstemmed Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer
title_short Extracellular Galectin 4 Drives Immune Evasion and Promotes T-cell Apoptosis in Pancreatic Cancer
title_sort extracellular galectin 4 drives immune evasion and promotes t-cell apoptosis in pancreatic cancer
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9808371/
https://www.ncbi.nlm.nih.gov/pubmed/36478037
http://dx.doi.org/10.1158/2326-6066.CIR-21-1088
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