Dual checkpoint blockade of CD47 and LILRB1 enhances CD20 antibody-dependent phagocytosis of lymphoma cells by macrophages
Antibody-dependent cellular phagocytosis (ADCP) by macrophages, an important effector function of tumor targeting antibodies, is hampered by ‘Don´t Eat Me!’ signals such as CD47 expressed by cancer cells. Yet, human leukocyte antigen (HLA) class I expression may also impair ADCP by engaging leukocyt...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.929339/full |
| _version_ | 1811257329903992832 |
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| author | Tobias Zeller Sebastian Lutz Ira A. Münnich Roland Windisch Patricia Hilger Tobias Herold Tobias Herold Tobias Herold Natyra Tahiri Jan C. Banck Oliver Weigert Oliver Weigert Oliver Weigert Andreas Moosmann Andreas Moosmann Andreas Moosmann Michael von Bergwelt-Baildon Michael von Bergwelt-Baildon Michael von Bergwelt-Baildon Cindy Flamann Heiko Bruns Christian Wichmann Niklas Baumann Thomas Valerius Denis M. Schewe Matthias Peipp Thies Rösner Andreas Humpe Christian Kellner |
| author_facet | Tobias Zeller Sebastian Lutz Ira A. Münnich Roland Windisch Patricia Hilger Tobias Herold Tobias Herold Tobias Herold Natyra Tahiri Jan C. Banck Oliver Weigert Oliver Weigert Oliver Weigert Andreas Moosmann Andreas Moosmann Andreas Moosmann Michael von Bergwelt-Baildon Michael von Bergwelt-Baildon Michael von Bergwelt-Baildon Cindy Flamann Heiko Bruns Christian Wichmann Niklas Baumann Thomas Valerius Denis M. Schewe Matthias Peipp Thies Rösner Andreas Humpe Christian Kellner |
| author_sort | Tobias Zeller |
| collection | DOAJ |
| description | Antibody-dependent cellular phagocytosis (ADCP) by macrophages, an important effector function of tumor targeting antibodies, is hampered by ‘Don´t Eat Me!’ signals such as CD47 expressed by cancer cells. Yet, human leukocyte antigen (HLA) class I expression may also impair ADCP by engaging leukocyte immunoglobulin-like receptor subfamily B (LILRB) member 1 (LILRB1) or LILRB2. Analysis of different lymphoma cell lines revealed that the ratio of CD20 to HLA class I cell surface molecules determined the sensitivity to ADCP by the combination of rituximab and an Fc-silent variant of the CD47 antibody magrolimab (CD47-IgGσ). To boost ADCP, Fc-silent antibodies against LILRB1 and LILRB2 were generated (LILRB1-IgGσ and LILRB2-IgGσ, respectively). While LILRB2-IgGσ was not effective, LILRB1-IgGσ significantly enhanced ADCP of lymphoma cell lines when combined with both rituximab and CD47-IgGσ. LILRB1-IgGσ promoted serial engulfment of lymphoma cells and potentiated ADCP by non-polarized M0 as well as polarized M1 and M2 macrophages, but required CD47 co-blockade and the presence of the CD20 antibody. Importantly, complementing rituximab and CD47-IgGσ, LILRB1-IgGσ increased ADCP of chronic lymphocytic leukemia (CLL) or lymphoma cells isolated from patients. Thus, dual checkpoint blockade of CD47 and LILRB1 may be promising to improve antibody therapy of CLL and lymphomas through enhancing ADCP by macrophages. |
| first_indexed | 2024-04-12T17:55:37Z |
| format | Article |
| id | doaj.art-741297763a5b405c9c2232db5b220176 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T17:55:37Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-741297763a5b405c9c2232db5b2201762022-12-22T03:22:22ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-10-011310.3389/fimmu.2022.929339929339Dual checkpoint blockade of CD47 and LILRB1 enhances CD20 antibody-dependent phagocytosis of lymphoma cells by macrophagesTobias Zeller0Sebastian Lutz1Ira A. Münnich2Roland Windisch3Patricia Hilger4Tobias Herold5Tobias Herold6Tobias Herold7Natyra Tahiri8Jan C. Banck9Oliver Weigert10Oliver Weigert11Oliver Weigert12Andreas Moosmann13Andreas Moosmann14Andreas Moosmann15Michael von Bergwelt-Baildon16Michael von Bergwelt-Baildon17Michael von Bergwelt-Baildon18Cindy Flamann19Heiko Bruns20Christian Wichmann21Niklas Baumann22Thomas Valerius23Denis M. Schewe24Matthias Peipp25Thies Rösner26Andreas Humpe27Christian Kellner28Division of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital, LMU Munich, Munich, GermanyDivision of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital, LMU Munich, Munich, GermanyDivision of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital, LMU Munich, Munich, GermanyDivision of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital, LMU Munich, Munich, GermanyDivision of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital, LMU Munich, Munich, GermanyDepartment of Medicine III, University Hospital, LMU Munich, Munich, GermanyGerman Cancer Consortium (DKTK), Partner Site Munich, Munich, GermanyGerman Cancer Research Center (DKFZ), Heidelberg, GermanyDepartment of Medicine III, University Hospital, LMU Munich, Munich, GermanyDepartment of Medicine III, University Hospital, LMU Munich, Munich, GermanyDepartment of Medicine III, University Hospital, LMU Munich, Munich, GermanyGerman Cancer Consortium (DKTK), Partner Site Munich, Munich, GermanyGerman Cancer Research Center (DKFZ), Heidelberg, GermanyDepartment of Medicine III, University Hospital, LMU Munich, Munich, GermanyDZIF – German Center for Infection Research, Munich, GermanyHelmholtz Zentrum München, Munich, GermanyDepartment of Medicine III, University Hospital, LMU Munich, Munich, GermanyGerman Cancer Consortium (DKTK), Partner Site Munich, Munich, GermanyGerman Cancer Research Center (DKFZ), Heidelberg, GermanyDepartment of Internal Medicine 5, University Hospital Erlangen, Erlangen, GermanyDepartment of Internal Medicine 5, University Hospital Erlangen, Erlangen, GermanyDivision of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital, LMU Munich, Munich, GermanyDivision of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, Christian Albrechts University and University Hospital Schleswig-Holstein, Kiel, GermanyDivision of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, Christian Albrechts University and University Hospital Schleswig-Holstein, Kiel, GermanyDepartment of Pediatrics, Otto-von-Guericke University Magdeburg, Magdeburg, Germany0Division of Antibody-Based Immunotherapy, Department of Internal Medicine II, Christian Albrechts University and University Hospital Schleswig-Holstein, Kiel, GermanyDivision of Stem Cell Transplantation and Immunotherapy, Department of Internal Medicine II, Christian Albrechts University and University Hospital Schleswig-Holstein, Kiel, GermanyDivision of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital, LMU Munich, Munich, GermanyDivision of Transfusion Medicine, Cell Therapeutics and Haemostaseology, University Hospital, LMU Munich, Munich, GermanyAntibody-dependent cellular phagocytosis (ADCP) by macrophages, an important effector function of tumor targeting antibodies, is hampered by ‘Don´t Eat Me!’ signals such as CD47 expressed by cancer cells. Yet, human leukocyte antigen (HLA) class I expression may also impair ADCP by engaging leukocyte immunoglobulin-like receptor subfamily B (LILRB) member 1 (LILRB1) or LILRB2. Analysis of different lymphoma cell lines revealed that the ratio of CD20 to HLA class I cell surface molecules determined the sensitivity to ADCP by the combination of rituximab and an Fc-silent variant of the CD47 antibody magrolimab (CD47-IgGσ). To boost ADCP, Fc-silent antibodies against LILRB1 and LILRB2 were generated (LILRB1-IgGσ and LILRB2-IgGσ, respectively). While LILRB2-IgGσ was not effective, LILRB1-IgGσ significantly enhanced ADCP of lymphoma cell lines when combined with both rituximab and CD47-IgGσ. LILRB1-IgGσ promoted serial engulfment of lymphoma cells and potentiated ADCP by non-polarized M0 as well as polarized M1 and M2 macrophages, but required CD47 co-blockade and the presence of the CD20 antibody. Importantly, complementing rituximab and CD47-IgGσ, LILRB1-IgGσ increased ADCP of chronic lymphocytic leukemia (CLL) or lymphoma cells isolated from patients. Thus, dual checkpoint blockade of CD47 and LILRB1 may be promising to improve antibody therapy of CLL and lymphomas through enhancing ADCP by macrophages.https://www.frontiersin.org/articles/10.3389/fimmu.2022.929339/fullantibody therapymacrophagesphagocytosisCD20CD47LILRB1 (ILT2) |
| spellingShingle | Tobias Zeller Sebastian Lutz Ira A. Münnich Roland Windisch Patricia Hilger Tobias Herold Tobias Herold Tobias Herold Natyra Tahiri Jan C. Banck Oliver Weigert Oliver Weigert Oliver Weigert Andreas Moosmann Andreas Moosmann Andreas Moosmann Michael von Bergwelt-Baildon Michael von Bergwelt-Baildon Michael von Bergwelt-Baildon Cindy Flamann Heiko Bruns Christian Wichmann Niklas Baumann Thomas Valerius Denis M. Schewe Matthias Peipp Thies Rösner Andreas Humpe Christian Kellner Dual checkpoint blockade of CD47 and LILRB1 enhances CD20 antibody-dependent phagocytosis of lymphoma cells by macrophages Frontiers in Immunology antibody therapy macrophages phagocytosis CD20 CD47 LILRB1 (ILT2) |
| title | Dual checkpoint blockade of CD47 and LILRB1 enhances CD20 antibody-dependent phagocytosis of lymphoma cells by macrophages |
| title_full | Dual checkpoint blockade of CD47 and LILRB1 enhances CD20 antibody-dependent phagocytosis of lymphoma cells by macrophages |
| title_fullStr | Dual checkpoint blockade of CD47 and LILRB1 enhances CD20 antibody-dependent phagocytosis of lymphoma cells by macrophages |
| title_full_unstemmed | Dual checkpoint blockade of CD47 and LILRB1 enhances CD20 antibody-dependent phagocytosis of lymphoma cells by macrophages |
| title_short | Dual checkpoint blockade of CD47 and LILRB1 enhances CD20 antibody-dependent phagocytosis of lymphoma cells by macrophages |
| title_sort | dual checkpoint blockade of cd47 and lilrb1 enhances cd20 antibody dependent phagocytosis of lymphoma cells by macrophages |
| topic | antibody therapy macrophages phagocytosis CD20 CD47 LILRB1 (ILT2) |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.929339/full |
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