Molecular Basis and Role of Siglec-7 Ligand Expression on Chronic Lymphocytic Leukemia B Cells
Siglec-7 (sialic acid–binding immunoglobulin-like lectin 7) is an immune checkpoint-like glycan recognition protein on natural killer (NK) cells. Cancer cells often upregulate Siglec ligands to subvert immunosurveillance, but the molecular basis of Siglec ligands has been elusive. In this study, we...
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| Format: | Article |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.840388/full |
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| author | Lan-Yi Chang Suh-Yuen Liang Shao-Chia Lu Huan Chuan Tseng Ho-Yang Tsai Ho-Yang Tsai Ho-Yang Tsai Chin-Ju Tang Marcelia Sugata Yi-Ju Chen Yu-Ju Chen Shang-Ju Wu Kuo-I Lin Kay-Hooi Khoo Kay-Hooi Khoo Takashi Angata Takashi Angata |
| author_facet | Lan-Yi Chang Suh-Yuen Liang Shao-Chia Lu Huan Chuan Tseng Ho-Yang Tsai Ho-Yang Tsai Ho-Yang Tsai Chin-Ju Tang Marcelia Sugata Yi-Ju Chen Yu-Ju Chen Shang-Ju Wu Kuo-I Lin Kay-Hooi Khoo Kay-Hooi Khoo Takashi Angata Takashi Angata |
| author_sort | Lan-Yi Chang |
| collection | DOAJ |
| description | Siglec-7 (sialic acid–binding immunoglobulin-like lectin 7) is an immune checkpoint-like glycan recognition protein on natural killer (NK) cells. Cancer cells often upregulate Siglec ligands to subvert immunosurveillance, but the molecular basis of Siglec ligands has been elusive. In this study, we investigated Siglec-7 ligands on chronic lymphocytic leukemia (CLL) B cells. CLL B cells express higher levels of Siglec-7 ligands compared with healthy donor B cells, and enzymatic removal of sialic acids or sialomucins makes them more sensitive to NK cell cytotoxicity. Gene knockout experiments have revealed that the sialyltransferase ST6GalNAc-IV is responsible for the biosynthesis of disialyl-T (Neu5Acα2–3Galβ1–3[Neu5Acα2–6]GalNAcα1–), which is the glycotope recognized by Siglec-7, and that CD162 and CD45 are the major carriers of this glycotope on CLL B cells. Analysis of public transcriptomic datasets indicated that the low expression of GCNT1 (encoding core 2 GlcNAc transferase, an enzyme that competes against ST6GalNAc-IV) and high expression of ST6GALNAC4 (encoding ST6GalNAc-IV) in CLL B cells, together enhancing the expression of the disialyl-T glycotope, are associated with poor patient prognosis. Taken together, our results determined the molecular basis of Siglec-7 ligand overexpression that protects CLL B cells from NK cell cytotoxicity and identified disialyl-T as a potential prognostic marker of CLL. |
| first_indexed | 2024-12-12T13:13:49Z |
| format | Article |
| id | doaj.art-c41da1f073eb457fb00cadf4cfe5d547 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-12T13:13:49Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-c41da1f073eb457fb00cadf4cfe5d5472022-12-22T00:23:29ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-05-011310.3389/fimmu.2022.840388840388Molecular Basis and Role of Siglec-7 Ligand Expression on Chronic Lymphocytic Leukemia B CellsLan-Yi Chang0Suh-Yuen Liang1Shao-Chia Lu2Huan Chuan Tseng3Ho-Yang Tsai4Ho-Yang Tsai5Ho-Yang Tsai6Chin-Ju Tang7Marcelia Sugata8Yi-Ju Chen9Yu-Ju Chen10Shang-Ju Wu11Kuo-I Lin12Kay-Hooi Khoo13Kay-Hooi Khoo14Takashi Angata15Takashi Angata16Institute of Biological Chemistry, Academia Sinica, Taipei, TaiwanInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanGenomics Research Center, Academia Sinica, Taipei, TaiwanInstitute of Biochemical Sciences, National Taiwan University, Taipei, TaiwanInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanInstitute of Chemistry, Academia Sinica, Taipei, TaiwanInstitute of Chemistry, Academia Sinica, Taipei, TaiwanDivision of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, TaiwanGenomics Research Center, Academia Sinica, Taipei, TaiwanInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanInstitute of Biochemical Sciences, National Taiwan University, Taipei, TaiwanInstitute of Biological Chemistry, Academia Sinica, Taipei, TaiwanInstitute of Biochemical Sciences, National Taiwan University, Taipei, TaiwanSiglec-7 (sialic acid–binding immunoglobulin-like lectin 7) is an immune checkpoint-like glycan recognition protein on natural killer (NK) cells. Cancer cells often upregulate Siglec ligands to subvert immunosurveillance, but the molecular basis of Siglec ligands has been elusive. In this study, we investigated Siglec-7 ligands on chronic lymphocytic leukemia (CLL) B cells. CLL B cells express higher levels of Siglec-7 ligands compared with healthy donor B cells, and enzymatic removal of sialic acids or sialomucins makes them more sensitive to NK cell cytotoxicity. Gene knockout experiments have revealed that the sialyltransferase ST6GalNAc-IV is responsible for the biosynthesis of disialyl-T (Neu5Acα2–3Galβ1–3[Neu5Acα2–6]GalNAcα1–), which is the glycotope recognized by Siglec-7, and that CD162 and CD45 are the major carriers of this glycotope on CLL B cells. Analysis of public transcriptomic datasets indicated that the low expression of GCNT1 (encoding core 2 GlcNAc transferase, an enzyme that competes against ST6GalNAc-IV) and high expression of ST6GALNAC4 (encoding ST6GalNAc-IV) in CLL B cells, together enhancing the expression of the disialyl-T glycotope, are associated with poor patient prognosis. Taken together, our results determined the molecular basis of Siglec-7 ligand overexpression that protects CLL B cells from NK cell cytotoxicity and identified disialyl-T as a potential prognostic marker of CLL.https://www.frontiersin.org/articles/10.3389/fimmu.2022.840388/fullchronic lymphocytic leukemianatural killer cellsSiglec-7sialomucinST6GalNAc-IVCore 2 GlcNAc transferase |
| spellingShingle | Lan-Yi Chang Suh-Yuen Liang Shao-Chia Lu Huan Chuan Tseng Ho-Yang Tsai Ho-Yang Tsai Ho-Yang Tsai Chin-Ju Tang Marcelia Sugata Yi-Ju Chen Yu-Ju Chen Shang-Ju Wu Kuo-I Lin Kay-Hooi Khoo Kay-Hooi Khoo Takashi Angata Takashi Angata Molecular Basis and Role of Siglec-7 Ligand Expression on Chronic Lymphocytic Leukemia B Cells Frontiers in Immunology chronic lymphocytic leukemia natural killer cells Siglec-7 sialomucin ST6GalNAc-IV Core 2 GlcNAc transferase |
| title | Molecular Basis and Role of Siglec-7 Ligand Expression on Chronic Lymphocytic Leukemia B Cells |
| title_full | Molecular Basis and Role of Siglec-7 Ligand Expression on Chronic Lymphocytic Leukemia B Cells |
| title_fullStr | Molecular Basis and Role of Siglec-7 Ligand Expression on Chronic Lymphocytic Leukemia B Cells |
| title_full_unstemmed | Molecular Basis and Role of Siglec-7 Ligand Expression on Chronic Lymphocytic Leukemia B Cells |
| title_short | Molecular Basis and Role of Siglec-7 Ligand Expression on Chronic Lymphocytic Leukemia B Cells |
| title_sort | molecular basis and role of siglec 7 ligand expression on chronic lymphocytic leukemia b cells |
| topic | chronic lymphocytic leukemia natural killer cells Siglec-7 sialomucin ST6GalNAc-IV Core 2 GlcNAc transferase |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.840388/full |
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