TIGIT blockade repolarizes AML-associated TIGIT+ M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis
Background Leukemia-associated macrophages (LAMs) represent an important cell population within the tumor microenvironment, but little is known about the phenotype, function, and plasticity of these cells. The present study provides an extensive characterization of macrophages in patients with acute...
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BMJ Publishing Group
2022-12-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/12/e004794.full |
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| author | Friedrich Haag Carsten Bokemeyer Lars Bullinger Franziska Brauneck Brit Fischer Marius Witt Jana Muschhammer Jennyfer Oelrich Pedro Henrique da Costa Avelar Sophia Tsoka Elisa Seubert Daniel J Smit Christin Ackermann Jasmin Wellbrock Walter Fiedler |
| author_facet | Friedrich Haag Carsten Bokemeyer Lars Bullinger Franziska Brauneck Brit Fischer Marius Witt Jana Muschhammer Jennyfer Oelrich Pedro Henrique da Costa Avelar Sophia Tsoka Elisa Seubert Daniel J Smit Christin Ackermann Jasmin Wellbrock Walter Fiedler |
| author_sort | Friedrich Haag |
| collection | DOAJ |
| description | Background Leukemia-associated macrophages (LAMs) represent an important cell population within the tumor microenvironment, but little is known about the phenotype, function, and plasticity of these cells. The present study provides an extensive characterization of macrophages in patients with acute myeloid leukemia (AML).Methods The phenotype and expression of coregulatory markers were assessed on bone marrow (BM)-derived LAM populations, using multiparametric flow cytometry. BM and blood aspirates were obtained from patients with newly diagnosed acute myeloid leukemia (pAML, n=59), patients in long-term remission (lrAML, n=8), patients with relapsed acute myeloid leukemia (rAML, n=7) and monocyte-derived macrophages of the blood from healthy donors (HD, n=17). LAM subpopulations were correlated with clinical parameters. Using a blocking anti-T-cell immunoreceptor with Ig and ITIM domains (TIGIT) antibody or mouse IgG2α isotype control, we investigated polarization, secretion of cytokines, and phagocytosis on LAMs and healthy monocyte-derived macrophages in vitro.Results In pAML and rAML, M1 LAMs were reduced and the predominant macrophage population consisted of immunosuppressive M2 LAMs defined by expression of CD163, CD204, CD206, and CD86. M2 LAMs in active AML highly expressed inhibitory receptors such as TIGIT, T-cell immunoglobulin and mucin-domain containing-3 protein (TIM-3), and lymphocyte-activation gene 3 (LAG-3). High expression of CD163 was associated with a poor overall survival (OS). In addition, increased frequencies of TIGIT+ M2 LAMs were associated with an intermediate or adverse risk according to the European Leukemia Network criteria and the FLT3 ITD mutation. In vitro blockade of TIGIT shifted the polarization of primary LAMs or peripheral blood-derived M2 macrophages toward the M1 phenotype and increased secretion of M1-associated cytokines and chemokines. Moreover, the blockade of TIGIT augmented the anti-CD47-mediated phagocytosis of AML cell lines and primary AML cells.Conclusion Our findings suggest that immunosuppressive TIGIT+ M2 LAMs can be redirected into an efficient effector population that may be of direct clinical relevance in the near future. |
| format | Article |
| id | doaj-art-2e7533273bea4d89a9f1519e8d362800 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-12-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-2e7533273bea4d89a9f1519e8d3628002024-11-24T02:45:10ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-12-01101210.1136/jitc-2022-004794TIGIT blockade repolarizes AML-associated TIGIT+ M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosisFriedrich Haag0Carsten Bokemeyer1Lars Bullinger2Franziska Brauneck3Brit Fischer4Marius Witt5Jana Muschhammer6Jennyfer Oelrich7Pedro Henrique da Costa Avelar8Sophia Tsoka9Elisa Seubert10Daniel J Smit11Christin Ackermann12Jasmin Wellbrock13Walter Fiedler14Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Internal Medicine II (Oncology/Hematology/BMT/Pneumology), University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Hematology, Oncology and Tumor Immunology, Charite Universitatsmedizin Berlin, Berlin, GermanyDepartment of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Informatics, Faculty of Natural and Mathematical Sciences, King`s College London, London, UKDepartment of Informatics, Faculty of Natural and Mathematical Sciences, King`s College London, London, UKDepartment of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInstitute of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyInfectious Diseases Unit, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyDepartment of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald University Cancer Center, University Medical Center Hamburg-Eppendorf, Hamburg, GermanyBackground Leukemia-associated macrophages (LAMs) represent an important cell population within the tumor microenvironment, but little is known about the phenotype, function, and plasticity of these cells. The present study provides an extensive characterization of macrophages in patients with acute myeloid leukemia (AML).Methods The phenotype and expression of coregulatory markers were assessed on bone marrow (BM)-derived LAM populations, using multiparametric flow cytometry. BM and blood aspirates were obtained from patients with newly diagnosed acute myeloid leukemia (pAML, n=59), patients in long-term remission (lrAML, n=8), patients with relapsed acute myeloid leukemia (rAML, n=7) and monocyte-derived macrophages of the blood from healthy donors (HD, n=17). LAM subpopulations were correlated with clinical parameters. Using a blocking anti-T-cell immunoreceptor with Ig and ITIM domains (TIGIT) antibody or mouse IgG2α isotype control, we investigated polarization, secretion of cytokines, and phagocytosis on LAMs and healthy monocyte-derived macrophages in vitro.Results In pAML and rAML, M1 LAMs were reduced and the predominant macrophage population consisted of immunosuppressive M2 LAMs defined by expression of CD163, CD204, CD206, and CD86. M2 LAMs in active AML highly expressed inhibitory receptors such as TIGIT, T-cell immunoglobulin and mucin-domain containing-3 protein (TIM-3), and lymphocyte-activation gene 3 (LAG-3). High expression of CD163 was associated with a poor overall survival (OS). In addition, increased frequencies of TIGIT+ M2 LAMs were associated with an intermediate or adverse risk according to the European Leukemia Network criteria and the FLT3 ITD mutation. In vitro blockade of TIGIT shifted the polarization of primary LAMs or peripheral blood-derived M2 macrophages toward the M1 phenotype and increased secretion of M1-associated cytokines and chemokines. Moreover, the blockade of TIGIT augmented the anti-CD47-mediated phagocytosis of AML cell lines and primary AML cells.Conclusion Our findings suggest that immunosuppressive TIGIT+ M2 LAMs can be redirected into an efficient effector population that may be of direct clinical relevance in the near future.https://jitc.bmj.com/content/10/12/e004794.full |
| spellingShingle | Friedrich Haag Carsten Bokemeyer Lars Bullinger Franziska Brauneck Brit Fischer Marius Witt Jana Muschhammer Jennyfer Oelrich Pedro Henrique da Costa Avelar Sophia Tsoka Elisa Seubert Daniel J Smit Christin Ackermann Jasmin Wellbrock Walter Fiedler TIGIT blockade repolarizes AML-associated TIGIT+ M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis Journal for ImmunoTherapy of Cancer |
| title | TIGIT blockade repolarizes AML-associated TIGIT+ M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis |
| title_full | TIGIT blockade repolarizes AML-associated TIGIT+ M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis |
| title_fullStr | TIGIT blockade repolarizes AML-associated TIGIT+ M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis |
| title_full_unstemmed | TIGIT blockade repolarizes AML-associated TIGIT+ M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis |
| title_short | TIGIT blockade repolarizes AML-associated TIGIT+ M2 macrophages to an M1 phenotype and increases CD47-mediated phagocytosis |
| title_sort | tigit blockade repolarizes aml associated tigit m2 macrophages to an m1 phenotype and increases cd47 mediated phagocytosis |
| url | https://jitc.bmj.com/content/10/12/e004794.full |
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