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Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Despite the successful application of immune checkpoint blockade in a range of human cancers, immunotherapy in PDAC remains unsuccessful. PDAC is characterized by a desmoplastic, hypoxic and highly immunosuppressive...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10632901/ https://www.ncbi.nlm.nih.gov/pubmed/37940346 http://dx.doi.org/10.1136/jitc-2023-007805 |
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author | Boelaars, Kelly Goossens-Kruijssen, Laura Wang, Di de Winde, Charlotte M Rodriguez, Ernesto Lindijer, Dimitri Springer, Babet van der Haar Àvila, Irene de Haas, Aram Wehry, Laetitia Boon, Louis Mebius, Reina E van Montfoort, Nadine Wuhrer, Manfred den Haan, Joke M M van Vliet, Sandra J van Kooyk, Yvette |
author_facet | Boelaars, Kelly Goossens-Kruijssen, Laura Wang, Di de Winde, Charlotte M Rodriguez, Ernesto Lindijer, Dimitri Springer, Babet van der Haar Àvila, Irene de Haas, Aram Wehry, Laetitia Boon, Louis Mebius, Reina E van Montfoort, Nadine Wuhrer, Manfred den Haan, Joke M M van Vliet, Sandra J van Kooyk, Yvette |
author_sort | Boelaars, Kelly |
collection | PubMed |
description | BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Despite the successful application of immune checkpoint blockade in a range of human cancers, immunotherapy in PDAC remains unsuccessful. PDAC is characterized by a desmoplastic, hypoxic and highly immunosuppressive tumor microenvironment (TME), where T-cell infiltration is often lacking (immune desert), or where T cells are located distant from the tumor islands (immune excluded). Converting the TME to an immune-inflamed state, allowing T-cell infiltration, could increase the success of immunotherapy in PDAC. METHOD: In this study, we use the KPC3 subcutaneous PDAC mouse model to investigate the role of tumor-derived sialic acids in shaping the tumor immune landscape. A sialic acid deficient KPC3 line was generated by genetic knock-out of the CMAS (cytidine monophosphate N-acetylneuraminic acid synthetase) enzyme, a critical enzyme in the synthesis of sialic acid-containing glycans. The effect of sialic acid-deficiency on immunotherapy efficacy was assessed by treatment with anti-programmed cell death protein 1 (PD-1) and agonistic CD40. RESULT: The absence of sialic acids in KPC3 tumors resulted in increased numbers of CD4(+) and CD8(+) T cells in the TME, and reduced frequencies of CD4(+) regulatory T cells (Tregs) within the T-cell population. Importantly, CD8(+) T cells were able to infiltrate the tumor islands in sialic acid-deficient tumors. These favorable alterations in the immune landscape sensitized sialic acid-deficient tumors to immunotherapy, which was ineffective in sialic acid-expressing KPC3 tumors. In addition, high expression of sialylation-related genes in human pancreatic cancer correlated with decreased CD8(+) T-cell infiltration, increased presence of Tregs, and poorer survival probability. CONCLUSION: Our results demonstrate that tumor-derived sialic acids mediate T-cell exclusion within the PDAC TME, thereby impairing immunotherapy efficacy. Targeting sialic acids represents a potential strategy to enhance T-cell infiltration and improve immunotherapy outcomes in PDAC. |
format | Online Article Text |
id | pubmed-10632901 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-106329012023-11-10 Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer Boelaars, Kelly Goossens-Kruijssen, Laura Wang, Di de Winde, Charlotte M Rodriguez, Ernesto Lindijer, Dimitri Springer, Babet van der Haar Àvila, Irene de Haas, Aram Wehry, Laetitia Boon, Louis Mebius, Reina E van Montfoort, Nadine Wuhrer, Manfred den Haan, Joke M M van Vliet, Sandra J van Kooyk, Yvette J Immunother Cancer Basic Tumor Immunology BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Despite the successful application of immune checkpoint blockade in a range of human cancers, immunotherapy in PDAC remains unsuccessful. PDAC is characterized by a desmoplastic, hypoxic and highly immunosuppressive tumor microenvironment (TME), where T-cell infiltration is often lacking (immune desert), or where T cells are located distant from the tumor islands (immune excluded). Converting the TME to an immune-inflamed state, allowing T-cell infiltration, could increase the success of immunotherapy in PDAC. METHOD: In this study, we use the KPC3 subcutaneous PDAC mouse model to investigate the role of tumor-derived sialic acids in shaping the tumor immune landscape. A sialic acid deficient KPC3 line was generated by genetic knock-out of the CMAS (cytidine monophosphate N-acetylneuraminic acid synthetase) enzyme, a critical enzyme in the synthesis of sialic acid-containing glycans. The effect of sialic acid-deficiency on immunotherapy efficacy was assessed by treatment with anti-programmed cell death protein 1 (PD-1) and agonistic CD40. RESULT: The absence of sialic acids in KPC3 tumors resulted in increased numbers of CD4(+) and CD8(+) T cells in the TME, and reduced frequencies of CD4(+) regulatory T cells (Tregs) within the T-cell population. Importantly, CD8(+) T cells were able to infiltrate the tumor islands in sialic acid-deficient tumors. These favorable alterations in the immune landscape sensitized sialic acid-deficient tumors to immunotherapy, which was ineffective in sialic acid-expressing KPC3 tumors. In addition, high expression of sialylation-related genes in human pancreatic cancer correlated with decreased CD8(+) T-cell infiltration, increased presence of Tregs, and poorer survival probability. CONCLUSION: Our results demonstrate that tumor-derived sialic acids mediate T-cell exclusion within the PDAC TME, thereby impairing immunotherapy efficacy. Targeting sialic acids represents a potential strategy to enhance T-cell infiltration and improve immunotherapy outcomes in PDAC. BMJ Publishing Group 2023-11-08 /pmc/articles/PMC10632901/ /pubmed/37940346 http://dx.doi.org/10.1136/jitc-2023-007805 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Basic Tumor Immunology Boelaars, Kelly Goossens-Kruijssen, Laura Wang, Di de Winde, Charlotte M Rodriguez, Ernesto Lindijer, Dimitri Springer, Babet van der Haar Àvila, Irene de Haas, Aram Wehry, Laetitia Boon, Louis Mebius, Reina E van Montfoort, Nadine Wuhrer, Manfred den Haan, Joke M M van Vliet, Sandra J van Kooyk, Yvette Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer |
title | Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer |
title_full | Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer |
title_fullStr | Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer |
title_full_unstemmed | Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer |
title_short | Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer |
title_sort | unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer |
topic | Basic Tumor Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10632901/ https://www.ncbi.nlm.nih.gov/pubmed/37940346 http://dx.doi.org/10.1136/jitc-2023-007805 |
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