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...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-11-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/11/e007805.full |
| _version_ | 1797426451404816384 |
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| author | Manfred Wuhrer Louis Boon Di Wang Yvette van Kooyk Ernesto Rodriguez Joke M M Den Haan Nadine van Montfoort Sandra J van Vliet Kelly Boelaars Laura Goossens-Kruijssen Charlotte M de Winde Dimitri Lindijer Babet Springer Irene van der Haar Àvila Aram de Haas Laetitia Wehry Reina E Mebius |
| author_facet | Manfred Wuhrer Louis Boon Di Wang Yvette van Kooyk Ernesto Rodriguez Joke M M Den Haan Nadine van Montfoort Sandra J van Vliet Kelly Boelaars Laura Goossens-Kruijssen Charlotte M de Winde Dimitri Lindijer Babet Springer Irene van der Haar Àvila Aram de Haas Laetitia Wehry Reina E Mebius |
| author_sort | Manfred Wuhrer |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T08:30:27Z |
| format | Article |
| id | doaj.art-13e463cc897642b5b08aea0a5c85d90b |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-09T08:30:27Z |
| publishDate | 2023-11-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-13e463cc897642b5b08aea0a5c85d90b2023-12-02T20:10:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-11-01111110.1136/jitc-2023-007805Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancerManfred Wuhrer0Louis Boon1Di Wang2Yvette van Kooyk3Ernesto Rodriguez4Joke M M Den Haan5Nadine van Montfoort6Sandra J van Vliet7Kelly Boelaars8Laura Goossens-Kruijssen9Charlotte M de Winde10Dimitri Lindijer11Babet Springer12Irene van der Haar Àvila13Aram de Haas14Laetitia Wehry15Reina E Mebius16Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The NetherlandsJJP Biologics, Warsaw, PolandCenter for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The NetherlandsMolecular Cell Biology & Immunology, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The NetherlandsMolecular Cell Biology & Immunology, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The NetherlandsMolecular Cell Biology & Immunology, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The NetherlandsDepartment of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The NetherlandsMolecular Cell Biology & Immunology, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The NetherlandsMolecular Cell Biology & Immunology, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The NetherlandsMolecular Cell Biology & Immunology, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The NetherlandsMolecular Cell Biology & Immunology, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The NetherlandsMolecular Cell Biology & Immunology, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The NetherlandsMolecular Cell Biology & Immunology, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The NetherlandsMolecular Cell Biology & Immunology, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The NetherlandsMolecular Cell Biology & Immunology, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The NetherlandsMolecular Cell Biology & Immunology, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The NetherlandsMolecular Cell Biology & Immunology, Amsterdam institute for Infection and Immunity, Cancer Center Amsterdam, Amsterdam UMC Location VUmc, Amsterdam, The NetherlandsBackground 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.https://jitc.bmj.com/content/11/11/e007805.full |
| spellingShingle | Manfred Wuhrer Louis Boon Di Wang Yvette van Kooyk Ernesto Rodriguez Joke M M Den Haan Nadine van Montfoort Sandra J van Vliet Kelly Boelaars Laura Goossens-Kruijssen Charlotte M de Winde Dimitri Lindijer Babet Springer Irene van der Haar Àvila Aram de Haas Laetitia Wehry Reina E Mebius Unraveling the impact of sialic acids on the immune landscape and immunotherapy efficacy in pancreatic cancer Journal for ImmunoTherapy of 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 |
| url | https://jitc.bmj.com/content/11/11/e007805.full |
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