Stahl, Gödel, and Balke-Want et al. performed multimodal analysis of pre- and post-CAR T cell-treated tissue from patients with relapsed or refractory aggressive B cell lymphoma (B-NHL) and identified a distinct CSF1R+CD14+CD68+ lymphoma-associated myeloid-monocytic (LAMM) cell population associated with poor outcomes in both human and murine B-NHL. Cell–cell communication analysis inferred that direct LAMM–T cell interactions via the PGE2–EP2/EP4 axis impaired CAR T cell functions. Anti-CD19 CAR T cell therapy with CSF1R blockade exhibited synergistic effects and improved survival in an autochthonous lymphoma mouse model.
Contributed by Shishir Pant
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 PGE(2)-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.
Author Info: (1) Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, C
Author Info: (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 Dsseldorf (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; Mildred Scheel School of Oncology Aachen Bonn Cologne Dsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany. (7) 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. (8) Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany. (9) Division of Clinical Pharmacology, Department of Medicine IV, LMU University Hospital, Member of the German Center for Lung Research (DZL), LMU Munich, Munich, Germany. (10) 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. (11) 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. (12) Institute of Pathology, University Hospital Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany. (13) 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. (14) Department of Medicine, Hematology and Oncology, University Hospital, Goethe University Frankfurt, Frankfurt am Main, Germany; Frankfurt Cancer Institute (FCI), Frankfurt am Main, Germany. (15) 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. (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; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. (17) 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. (18) 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. (19) 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. (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; Department I of Internal Medicine, Translational Research for Infectious Diseases and Oncology (TRIO), University Hospital Clinic of Cologne, Cologne, Germany. (21) Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany. (22) Department of Nuclear Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. (23) Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada. (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; 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. (25) 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. (26) Institute of Pathology, University Hospital Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany. (27) Institute for Diagnostic and Interventional Radiology, Faculty of Medicine and University Hospital Cologne, University Cologne, Cologne, Germany. (28) 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. (29) 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. (30) 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. (31) 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. (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; 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. (33) 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. (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. (35) 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. (36) Institute of Pathology, University Hospital Cologne, Faculty of Medicine, 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; 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. (38) 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. (39) 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. (40) Institute of Pathology, University Hospital Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany. (41) Department of Chemistry, University of Toronto, Toronto, ON M5S 3H6, Canada. (42) Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Dsseldorf (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. (43) Miltenyi Biotec B.V. & Co. KG, Bergisch Gladbach, Germany. (44) Institute for Diagnostic and Interventional Radiology, Faculty of Medicine and University Hospital Cologne, University Cologne, Cologne, Germany. (45) 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. (46) 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. (47) Institute of Pathology, University Hospital Cologne, Faculty of Medicine, University of Cologne, Cologne, Germany; National Center for Tumor Diseases (NCT), NCT West, Cologne, Germany. (48) 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. (49) 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. (50) 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. (51) 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. (52) 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. (53) 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. (54) 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. (55) 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. (56) 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.
