T-cell prolymphocytic leukemia (T-PLL) is a poor prognostic disease with very limited options of efficient therapies. Most patients are refractory to chemotherapies and despite high response rates after alemtuzumab, virtually all patients relapse. Therefore, there is an unmet medical need for novel therapies in T-PLL. As the chemokine receptor CCR7 is a molecule expressed in a wide range of malignancies and relevant in many tumor processes, the present study addressed the biologic role of this receptor in T-PLL. Furthermore, we elucidated the mechanisms of action mediated by an anti-CCR7 monoclonal antibody (mAb) and evaluated whether its anti-tumor activity would warrant development towards clinical applications in T-PLL. Our results demonstrate that CCR7 is a prognostic biomarker for overall survival in T-PLL patients and a functional receptor involved in the migration, invasion, and survival of leukemic cells. Targeting CCR7 with a mAb inhibited ligand-mediated signaling pathways and induced tumor cell killing in primary samples. In addition, directing antibodies against CCR7 was highly effective in T-cell leukemia xenograft models. Together, these findings make CCR7 an attractive molecule for novel mAb-based therapeutic applications in T-PLL, a disease where recent drug screen efforts and studies addressing new compounds have focused on chemotherapy or small molecules. Supplementary information: Supplementary information accompanies this paper at 10.1186/s40364-020-00234-z.

Department 1 of Internal Medicine Center for Integrated Oncology The University of Cologne Cologne Germany

Department of Cell Biology and Immunology Centro de Biología Molecular Severo Ochoa CSIC UAM Madrid Spain

Department of Hemato Oncology Faculty Hospital Olomouc Faculty of Medicine and Dentistry Palacky University Olomouc Czech Republic

Department of Hematology Hematology Research Unit Helsinki Helsinki University Hospital Comprehensive Cancer Center Helsinki Finland

Department of Hematology Hematology Research Unit Helsinki Helsinki University Hospital Comprehensive Cancer Center Helsinki Finland Translational Immunology Research Program and Department of Clinical Chemistry University of Helsinki Helsinki Finland

Hematology Department Hospital Universitario de La Princesa IIS IP Madrid Spain

IMMED S L Immunological and Medicinal Products Madrid Spain

Immune System Development and Function Unit Centro de Biología Molecular Severo Ochoa CSIC UAM Madrid Spain

Immunology Department Hospital Universitario de La Princesa IIS IP C Diego de León 62 28006 Madrid Spain

Immunology Department Hospital Universitario de La Princesa IIS IP C Diego de León 62 28006 Madrid Spain IMMED S L Immunological and Medicinal Products Madrid Spain

Immunology Department Hospital Universitario de La Princesa IIS IP C Diego de León 62 28006 Madrid Spain Universidad Autónoma de Madrid Madrid Spain

Methodology Unit Hospital Universitario de La Princesa IIS IP Madrid Spain