Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany.
Department of Dermatology and Venerology, HELIOS Klinikum Krefeld, Krefeld, Germany.
Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany.
Department of Dermatology, Venerology and Allergology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany; Section of Clinical and Experimental Dermatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
Department of Dermatology, Center for Dermatooncology, University Hospital Tübingen, Tübingen, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Department of Pharmacology, Physiology and Microbiology, Division Pharmacology, Karl Landsteiner University of Health Sciences, Krems, Austria.
Department of Pharmacology, Physiology and Microbiology, Division Pharmacology, Karl Landsteiner University of Health Sciences, Krems, Austria.
Department of Pharmacology, Physiology and Microbiology, Division Pharmacology, Karl Landsteiner University of Health Sciences, Krems, Austria.
Sutro Biopharma, CA, South San Franciso, United States.
Institute of Pathology, Charité - Universitätsmedizin Berlin, Corporate member of Freie Universität, Humboldt-Universität zu Berlin, Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Institute of Human Genetics, Ulm University, Ulm University Medical Center, Ulm, Germany.
Institute of Human Genetics, Ulm University, Ulm University Medical Center, Ulm, Germany.
Department of Dermatology, Venerology and Allergology, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany; Section of Clinical and Experimental Dermatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany.
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Translational Skin Cancer Research, University Medicine Essen, Essen, Germany.
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant Lymphomas, Berlin, Germany; Hematology, Oncology and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität, Humboldt-Universität zu Berlin, Berlin, Germany; Experimental and Clinical Research Center (ECRC), a joint cooperation between Charité and MDC, Berlin, Germany.
Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Translational Skin Cancer Research, University Medicine Essen, Essen, Germany.
Department of Pathology and Neuropathology, University Hospital and Comprehensive Cancer Center Tübingen, Tübingen, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Cluster of Excellence iFIT (EXC 2180), Image-Guided and Functionally Instructed Tumor Therapies, University of Tübingen, Tübingen, Germany.
Department of Dermatology and Venerology, HELIOS Klinikum Krefeld, Krefeld, Germany; Institute for Molecular Medicine, Medical School Hamburg, Hamburg, Germany.
Department of Pathology, Medical University of Vienna, Vienna, Austria.
Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Biology of Malignant Lymphomas, Berlin, Germany; Hematology, Oncology and Cancer Immunology, Charité – Universitätsmedizin Berlin, Corporate member of Freie Universität, Humboldt-Universität zu Berlin, Berlin, Germany; Experimental and Clinical Research Center (ECRC), a joint cooperation between Charité and MDC, Berlin, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
Background Prognosis and quality of life in patients with advanced cutaneous T-cell lymphoma (CTCL), particularly in those with Sézary syndrome (SS) or advanced-stage mycosis fungoides (MF), are poor. Monoclonal antibodies or antibody–drug conjugates (ADCs) have been added into CTCL treatment algorithms, but the spectrum of antibody-targetable cell surface antigens in T-cell non-Hodgkin lymphomas (T-NHLs) is limited.
Objectives To evaluate the expression of the major histocompatibility complex class II chaperone CD74 in common subtypes of CTCL by various methods, and to explore the efficacy of targeting CD74 in CTCL cells with an anti-CD74 ADC in vitro and in vivo.
Methods We comprehensively investigated the expression of CD74 in well-defined CTCL cell lines by polymerase chain reaction, immunoblotting and flow cytometry. More than 140 primary CTCL samples of all common subtypes were analysed by immunohistochemistry, flow cytometry, immunofluorescence and ‘co-detection by indexing’ (CODEX) multiplexed tissue imaging, as well as by single-cell RNA sequencing (scRNAseq) analyses. DNA methylation of CTCL cell lines was interrogated by the generation of genome-wide methylation profiling. The effect of a maytansinoid-conjugated humanized ADC against CD74 was investigated in CTCL cell lines in vitro, alone or in combination with gemcitabine, and in vivo after xenotransplantation of CTCL cell lines in NOD-scid Il2rgnull mice.
Results We demonstrated that CD74 is widely and robustly expressed in CTCL cells. In addition, CD74 expression in SS and MF was confirmed by scRNAseq data analysis and was correlated in CTCL cell lines with CD74 DNA hypomethylation. CD74 was rapidly internalized in CTCL cells and CD74 targeting by the ADC STRO-001 efficiently killed CTCL-derived cell lines. Finally, targeting of CD74 synergized with conventional chemotherapy in vitro and eradicated murine xenotransplants of CTCL cell lines in vivo.
Conclusions CD74 is expressed in common CTCL subtypes. Targeting CD74 efficiently killed CTCL cells in vitro and in vivo. We therefore suggest the targeting of CD74 to be a highly promising treatment strategy for CTCL.
Oxford University Press, 2025. Vol. 192, no 5, p. 883-895