PDL1-expressing macrophages infiltrate diffuse large B-cell lymphoma and promote lymphoma growth in a MYC-driven experimental model
Abstract The infiltration of diffuse large- and other mature B-cell lymphomas with T- and myeloid cells is a key tumor microenvironmental feature but is not currently factored into treatment decisions. Here, we have used multiplex immunofluorescence microscopy to quantify the immune infiltrates of &...
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Nature Publishing Group
2025-04-01
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| Series: | Blood Cancer Journal |
| Online Access: | https://doi.org/10.1038/s41408-025-01281-1 |
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| author | Ningxuan Cui Peter Leary Vanesa-Sindi Ivanova Kristin Stirm Lydia Kirsche Nicola Aceto Frank Stenner Lothar C. Dieterich Michael Detmar Ekaterina Petrova Sarah Mundt Melanie Greter Alexandar Tzankov Anne Müller |
| author_facet | Ningxuan Cui Peter Leary Vanesa-Sindi Ivanova Kristin Stirm Lydia Kirsche Nicola Aceto Frank Stenner Lothar C. Dieterich Michael Detmar Ekaterina Petrova Sarah Mundt Melanie Greter Alexandar Tzankov Anne Müller |
| author_sort | Ningxuan Cui |
| collection | DOAJ |
| description | Abstract The infiltration of diffuse large- and other mature B-cell lymphomas with T- and myeloid cells is a key tumor microenvironmental feature but is not currently factored into treatment decisions. Here, we have used multiplex immunofluorescence microscopy to quantify the immune infiltrates of >260 diffuse large B-cell- (DLBCL), follicular- (FL) and mantle cell lymphomas (MCL), and chronic lymphocytic leukemias (CLL) relative to clinical outcomes, mutational landscape and phenotype. MCL were found to be the “coldest” and DLBCL the “hottest” entities. The lymphoma microenvironment of DLBCL featured numerically dominant populations of CD8+ and T-follicular helper (Tfh) T-cells that were indicative of superior prognosis. Mutations in EZH2, PTEN and KMT2D were overrepresented in DLBCL with low CD8+ T-cell infiltration. A unique feature of DLBCL was its infiltration by large numbers of PDL1+ macrophages that constituted up to 70% of total cellularity. PDL1+ macrophage infiltration was mutually exclusive with regulatory T-cell infiltration. The inducible ablation of PDL1 on macrophages was sufficient to improve immune control of MYC-expressing lymphoma in a syngeneic immunocompetent model. These results implicate the macrophage/CD8+ T-cell axis as a key pathogenetic determinant and immunotherapeutic target in a subset of DLBCL patients with poor prognosis. |
| format | Article |
| id | doaj-art-e41fe8356e144e5697f5f20c39e51116 |
| institution | DOAJ |
| issn | 2044-5385 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Blood Cancer Journal |
| spelling | doaj-art-e41fe8356e144e5697f5f20c39e511162025-08-20T03:18:34ZengNature Publishing GroupBlood Cancer Journal2044-53852025-04-0115111510.1038/s41408-025-01281-1PDL1-expressing macrophages infiltrate diffuse large B-cell lymphoma and promote lymphoma growth in a MYC-driven experimental modelNingxuan Cui0Peter Leary1Vanesa-Sindi Ivanova2Kristin Stirm3Lydia Kirsche4Nicola Aceto5Frank Stenner6Lothar C. Dieterich7Michael Detmar8Ekaterina Petrova9Sarah Mundt10Melanie Greter11Alexandar Tzankov12Anne Müller13Institute of Molecular Cancer Research, University of ZürichInstitute of Molecular Cancer Research, University of ZürichInstitute of Medical Genetics and Pathology, University Hospital BaselInstitute of Molecular Cancer Research, University of ZürichInstitute of Molecular Cancer Research, University of ZürichInstitute of Molecular Health Sciences, Swiss Federal Institute of Technology ZürichClinic for Medical Oncology, University Hospital BaselEuropean Center for Angioscience and Mannheim Institute of Innate Immunoscience, Medical Faculty Mannheim, Heidelberg UniversityInstitute of Pharmaceutical Sciences, Swiss Federal Institute of Technology ZürichInstitute of Experimental Immunology, University of ZürichInstitute of Experimental Immunology, University of ZürichInstitute of Experimental Immunology, University of ZürichInstitute of Medical Genetics and Pathology, University Hospital BaselInstitute of Molecular Cancer Research, University of ZürichAbstract The infiltration of diffuse large- and other mature B-cell lymphomas with T- and myeloid cells is a key tumor microenvironmental feature but is not currently factored into treatment decisions. Here, we have used multiplex immunofluorescence microscopy to quantify the immune infiltrates of >260 diffuse large B-cell- (DLBCL), follicular- (FL) and mantle cell lymphomas (MCL), and chronic lymphocytic leukemias (CLL) relative to clinical outcomes, mutational landscape and phenotype. MCL were found to be the “coldest” and DLBCL the “hottest” entities. The lymphoma microenvironment of DLBCL featured numerically dominant populations of CD8+ and T-follicular helper (Tfh) T-cells that were indicative of superior prognosis. Mutations in EZH2, PTEN and KMT2D were overrepresented in DLBCL with low CD8+ T-cell infiltration. A unique feature of DLBCL was its infiltration by large numbers of PDL1+ macrophages that constituted up to 70% of total cellularity. PDL1+ macrophage infiltration was mutually exclusive with regulatory T-cell infiltration. The inducible ablation of PDL1 on macrophages was sufficient to improve immune control of MYC-expressing lymphoma in a syngeneic immunocompetent model. These results implicate the macrophage/CD8+ T-cell axis as a key pathogenetic determinant and immunotherapeutic target in a subset of DLBCL patients with poor prognosis.https://doi.org/10.1038/s41408-025-01281-1 |
| spellingShingle | Ningxuan Cui Peter Leary Vanesa-Sindi Ivanova Kristin Stirm Lydia Kirsche Nicola Aceto Frank Stenner Lothar C. Dieterich Michael Detmar Ekaterina Petrova Sarah Mundt Melanie Greter Alexandar Tzankov Anne Müller PDL1-expressing macrophages infiltrate diffuse large B-cell lymphoma and promote lymphoma growth in a MYC-driven experimental model Blood Cancer Journal |
| title | PDL1-expressing macrophages infiltrate diffuse large B-cell lymphoma and promote lymphoma growth in a MYC-driven experimental model |
| title_full | PDL1-expressing macrophages infiltrate diffuse large B-cell lymphoma and promote lymphoma growth in a MYC-driven experimental model |
| title_fullStr | PDL1-expressing macrophages infiltrate diffuse large B-cell lymphoma and promote lymphoma growth in a MYC-driven experimental model |
| title_full_unstemmed | PDL1-expressing macrophages infiltrate diffuse large B-cell lymphoma and promote lymphoma growth in a MYC-driven experimental model |
| title_short | PDL1-expressing macrophages infiltrate diffuse large B-cell lymphoma and promote lymphoma growth in a MYC-driven experimental model |
| title_sort | pdl1 expressing macrophages infiltrate diffuse large b cell lymphoma and promote lymphoma growth in a myc driven experimental model |
| url | https://doi.org/10.1038/s41408-025-01281-1 |
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