CSF1R⁺ myeloid-monocytic cells drive CAR-T cell resistance in aggressive B cell lymphoma

David Stahl¹, Philipp Gödel², Hyatt Balke-Want³, Rahil Gholamipoorfard⁴, Paul Segbers⁵, Luis Tetenborg⁵, Mirjam Koker⁶, Janina Dörr⁷, Lisa Gregor⁷, Daniel Bachurski⁸, France Rose⁹, Adrian G Simon¹⁰, Zinaida Good¹¹, Josefine Jakob¹², Björn Häupl¹³, Marieke Nill⁶, Ruth Flümann¹⁴, Tobias Riet⁶, Dinah Lange¹⁵, Stuart J Blakemore¹⁶, Herrad Baurmann¹⁷, Conrad-Amadeus Voltin¹⁸, Nicole Potter¹⁹, Lilli Schlözer⁵, Max Freihammer²⁰, Svenja Wagener-Ryczek¹⁰, Andra-Iza Iuga²¹, Jan-Michel Heger²², Hanna Ludwig², Julia K Schleifenbaum²³, Jessica Propp², Paul J Bröckelmann¹⁴, Ron D Jachimowicz²⁴, Gero Knittel²⁵, Sven Borchmann²⁰, Sabine Merkelbach-Bruse¹⁰, Christian Pallasch²⁶, Martin Peifer²⁷, Jan Rybniker¹⁵, Alexander Quaas¹⁰, Mark Nitz¹⁹, Johannes Brägelmann²⁸, Werner Müller¹⁷, Thorsten Persigehl²¹, Katarzyna Bozek²⁹, Sebastian J Theobald¹⁵, Reinhard Büttner³⁰, Thomas Oellerich³¹, Michael Hallek³², Sebastian Kobold³³, Markus Chmielewski⁶, Hans Christian Reinhardt³⁴, Crystal Mackall³⁵, Nima Abedpour³⁶, Peter Borchmann²³, Roland T Ullrich³⁷

Affiliations

¹ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Else Kröner Forschungskolleg Clonal Evolution in Cancer, University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.
² Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
³ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
⁴ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁵ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.
⁶ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
⁷ Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany.
⁸ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
⁹ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; University of Cologne, Institute for Biomedical Informatics, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
¹⁰ Institute of Pathology, University Hospital Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany.
¹¹ Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA.
¹² Department of Medicine, Hematology and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany; Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany.
¹³ Department of Medicine, Hematology and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany; Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany; German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, a partnership between DKFZ and UCT Frankfurt-Marburg, Germany, Frankfurt am Main, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁴ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany; Max Planck Institute for Biology of Ageing, Cologne, Germany.
¹⁵ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Department I of Internal Medicine, Division of Infectious Diseases, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany; German Center for Infection Research (DZIF), Bonn-Cologne, Germany.
¹⁶ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Department I of Internal Medicine, Translational Research for Infectious Diseases and Oncology (TRIO), University Hospital Clinic of Cologne, Cologne, Germany.
¹⁷ Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany.
¹⁸ Department of Nuclear Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁹ Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
²⁰ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
²¹ Institute for Diagnostic and Interventional Radiology, Faculty of Medicine and University Hospital Cologne, University Cologne, Cologne, Germany.
²² Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Else Kröner Forschungskolleg Clonal Evolution in Cancer, University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.
²³ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
²⁴ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Max Planck Institute for Biology of Ageing, Cologne, Germany.
²⁵ Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Department of Hematology and Stem Cell Transplantation, West German Cancer Center, German Cancer Consortium Partner Site Essen, Center for Molecular Biotechnology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
²⁶ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Department I of Internal Medicine, Translational Research for Infectious Diseases and Oncology (TRIO), University Hospital Clinic of Cologne, Cologne, Germany.
²⁷ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
²⁸ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
²⁹ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany; University of Cologne, Institute for Biomedical Informatics, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
³⁰ Institute of Pathology, University Hospital Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany; National Center for Tumor Diseases (NCT), NCT West, Cologne, Germany.
³¹ Department of Medicine, Hematology and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany; Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany; German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, a partnership between DKFZ and UCT Frankfurt-Marburg, Germany, Frankfurt am Main, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; University Cancer Center (UCT), Frankfurt am Main, Germany.
³² Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany; National Center for Tumor Diseases (NCT), NCT West, Cologne, Germany.
³³ Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, a partnership between the DKFZ Heidelberg and the University Hospital of the LMU, Munich, Germany; Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München - German Research Center for Environmental Health Neuherberg, Munich, Germany.
³⁴ Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Department of Hematology and Stem Cell Transplantation, West German Cancer Center, German Cancer Consortium Partner Site Essen, Center for Molecular Biotechnology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; National Center for Tumor Diseases (NCT), NCT West, Cologne, Germany.
³⁵ Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford University, Stanford, CA, USA; Department of Medicine, Stanford University, Stanford, CA, USA.
³⁶ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
³⁷ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; National Center for Tumor Diseases (NCT), NCT West, Cologne, Germany. Electronic address: roland.ullrich@uk-koeln.de.

PMID: 40513575
DOI: 10.1016/j.ccell.2025.05.013

Free article

CSF1R⁺ myeloid-monocytic cells drive CAR-T cell resistance in aggressive B cell lymphoma

David Stahl et al. Cancer Cell. 2025.

Free article

. 2025 Aug 11;43(8):1476-1494.e10.

doi: 10.1016/j.ccell.2025.05.013. Epub 2025 Jun 12.

Authors

Affiliations

¹ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Else Kröner Forschungskolleg Clonal Evolution in Cancer, University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.
² Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
³ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA.
⁴ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁵ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.
⁶ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
⁷ Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany.
⁸ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.
⁹ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; University of Cologne, Institute for Biomedical Informatics, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
¹⁰ Institute of Pathology, University Hospital Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany.
¹¹ Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA.
¹² Department of Medicine, Hematology and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany; Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany.
¹³ Department of Medicine, Hematology and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany; Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany; German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, a partnership between DKFZ and UCT Frankfurt-Marburg, Germany, Frankfurt am Main, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
¹⁴ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany; Max Planck Institute for Biology of Ageing, Cologne, Germany.
¹⁵ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Department I of Internal Medicine, Division of Infectious Diseases, Medical Faculty and University Hospital Cologne, University of Cologne, Cologne, Germany; German Center for Infection Research (DZIF), Bonn-Cologne, Germany.
¹⁶ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Department I of Internal Medicine, Translational Research for Infectious Diseases and Oncology (TRIO), University Hospital Clinic of Cologne, Cologne, Germany.
¹⁷ Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany.
¹⁸ Department of Nuclear Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹⁹ Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada.
²⁰ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
²¹ Institute for Diagnostic and Interventional Radiology, Faculty of Medicine and University Hospital Cologne, University Cologne, Cologne, Germany.
²² Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Else Kröner Forschungskolleg Clonal Evolution in Cancer, University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.
²³ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
²⁴ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany; Max Planck Institute for Biology of Ageing, Cologne, Germany.
²⁵ Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Department of Hematology and Stem Cell Transplantation, West German Cancer Center, German Cancer Consortium Partner Site Essen, Center for Molecular Biotechnology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
²⁶ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Department I of Internal Medicine, Translational Research for Infectious Diseases and Oncology (TRIO), University Hospital Clinic of Cologne, Cologne, Germany.
²⁷ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
²⁸ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
²⁹ Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany; University of Cologne, Institute for Biomedical Informatics, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
³⁰ Institute of Pathology, University Hospital Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany; National Center for Tumor Diseases (NCT), NCT West, Cologne, Germany.
³¹ Department of Medicine, Hematology and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany; Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany; German Cancer Consortium (DKTK), partner site Frankfurt/Mainz, a partnership between DKFZ and UCT Frankfurt-Marburg, Germany, Frankfurt am Main, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany; University Cancer Center (UCT), Frankfurt am Main, Germany.
³² Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany; National Center for Tumor Diseases (NCT), NCT West, Cologne, Germany.
³³ Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, a partnership between the DKFZ Heidelberg and the University Hospital of the LMU, Munich, Germany; Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München - German Research Center for Environmental Health Neuherberg, Munich, Germany.
³⁴ Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Department of Hematology and Stem Cell Transplantation, West German Cancer Center, German Cancer Consortium Partner Site Essen, Center for Molecular Biotechnology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany; National Center for Tumor Diseases (NCT), NCT West, Cologne, Germany.
³⁵ Stanford Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Stanford University, Stanford, CA, USA; Department of Medicine, Stanford University, Stanford, CA, USA.
³⁶ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Department of Translational Genomics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
³⁷ Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; National Center for Tumor Diseases (NCT), NCT West, Cologne, Germany. Electronic address: roland.ullrich@uk-koeln.de.

PMID: 40513575
DOI: 10.1016/j.ccell.2025.05.013

Abstract

Despite the improvement, approximately 60% of patients with relapsed or refractory (r/r) aggressive B cell lymphoma (B-NHL) do not achieve durable benefit from CAR-T cell therapy. To elucidate factors associated with CAR-T therapy resistance, we conducted high-dimensional analyses of pre- and post-CAR-T cell specimens. In patients with non-durable response, we identified a prognostically relevant lymphoma-associated myeloid-monocytic (LAMM) gene signature. In-depth profiling revealed a distinct CSF1R⁺CD14⁺CD68⁺ LAMM cell population in both human and murine B-NHL that inhibits CAR-T cell function and correlates with poor outcome. Cell-cell inference analysis uncovered that LAMM cells impair CAR-T cell function through a direct LAMM-T cell interaction via the PGE₂-EP2/EP4 axis. In an autochthonous lymphoma mouse model, combined anti-CD19 CAR-T cell therapy with CSF1R blockade exhibited synergistic effects and improved survival. These findings provide strong rationale for combining anti-CD19 CAR-T cells with CSF1R inhibitors in treating r/r aggressive B-NHL patients.

Keywords: CAR-T cell; CSF1R; aggressive B-NHL; lymphoma tumor microenvironment; myeloid cells.

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Conflict of interest statement

Declaration of interests H.B.-W. received research funding from Wilson Wolf Manufacturing, LLC (G-Rex Grant Program). H.C.R. received consulting and lecture fees from Abbvie, AstraZeneca, Vertex, and Merck, received research funding from AstraZeneca and Gilead Pharmaceuticals and is a co-founder of CDL Therapeutics GmbH. J.-M.H. received research funding from Incyte, MorphoSys, and Novartis, received honoraria and/or is an advisor or consultant for Incyte, SERB Pharmaceuticals, SOBI, Novartis, Genmab, and Miltenyi Biotec, and received travel support from Novartis, SERB pharmaceuticals, and SOBI. J.B. received research funding from Bayer and for travel from Merck outside of the submitted work. A.-I.I. is part of the speakers’ bureau at Philips Healthcare. S.K. received honoraria from Cymab, Plectonic, TCR2 Inc., Novartis, BMS, Miltenyi, and GSK, is inventor of several patents in the field of immuno-oncology, received license fees from TCR2 Inc. and Carina Biotech, and received research support from TCR2 Inc., Plectonic GmbH, Catalym GmbH, Arcus Bioscience, and Tabby Therapeutics for work unrelated to the manuscript. The remaining authors declare no competing interest.

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CSF1R⁺ myeloid-monocytic cells drive CAR-T cell resistance in aggressive B cell lymphoma

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CSF1R⁺ myeloid-monocytic cells drive CAR-T cell resistance in aggressive B cell lymphoma

Authors

Affiliations

Abstract

Conflict of interest statement

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LinkOut - more resources

Full Text Sources

Research Materials

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