Bone Marrow Transplantation https://doi.org/10.1038/s41409-020-0830-8 ARTICLE Evaluation of therapeutic targeting of CCR7 in acute graft-versus-host disease Carlos Cuesta-Mateos 1,2 ● Itxaso Portero-Sainz 1 ● Marina García-Peydró 3 ● Juan Alcain 3 ● Patricia Fuentes 3 ● Raquel Juárez-Sánchez 1,2 ● Yaiza Pérez-García 1 ● Tamara Mateu-Albero 1 ● Paula Díaz-Fernández 1 ● Lorena Vega-Piris 4 ● Blanca A. Sánchez-López 1 ● Ana Marcos-Jiménez 1 ● Laura Cardeñoso 5 ● Valle Gómez-García de Soria 6 ● María Luisa Toribio 3 ● Cecilia Muñoz-Calleja 1 Received: 18 July 2019 / Revised: 22 January 2020 / Accepted: 4 February 2020 © The Author(s), under exclusive licence to Springer Nature Limited 2020 Abstract Graft-versus-host disease (GVHD) is the main complication after allogeneic hematopoietic stem cell transplantation. We previously unveiled a correlation between proportions of C-C motif chemokine receptor 7 (CCR7) + T cells in the apheresis and the risk of developing GVHD. We wanted to evaluate in vivo whether apheresis with low proportion of CCR7 + cells or treatment with an anti-human CCR7 monoclonal antibody (mAb) were suitable strategies to prevent or treat acute GVHD in preclinical xenogeneic models. Therapeutic anti-CCR7 mAb was the most effective strategy in both prophylactic and therapeutic settings where antibody drastically reduced in vivo lymphoid organ infiltration of donor CCR7 + T cells, extended lifespan and solved clinical signs. The antibody neutralized in vitro migration of naïve and central memory T cells toward CCR7 ligands and depleted target CCR7 + subsets through complement activation. Both mechanisms of action spared CCR7 - subsets, including effector memory and effector memory CD45RA + T cells which may mediate graft versus leukemia effect and immunity against infections. Accordingly, the numbers of donor CCR7 + T cells in the apheresis were not associated to cytomegalovirus reactivation or the recurrence of the underlying disease. These findings provide a promising new strategy to prevent and treat acute GVHD, a condition where new specific, safety and effective treatment is needed. Introduction Acute graft-versus-host disease GVHD (aGVHD) is initiated by an early migration of donor T cells to the host lymph nodes (LN) and other secondary lymphoid organs where they get activated by allo-antigens on host antigen- presenting cells (APC) [1–5]. LN-specific homing of T cells and APC is orchestrated by the chemokine receptor CCR7 and its ligands, the chemokines (C-C motif) ligand 19 (CCL19) and CCL21. In addition, CCR7 favors close physical contact between APCs and T cells in the LN paracortex thus allowing specific T-cell acti- vation [6–8]. CCR7 + naïve (T N ) and central memory T cells (T CM ) are considered the primary mediators of aGVHD [9–18]. Conversely, CCR7 - effector memory T cells (T EM ) and CCR7 - CD45RA + T EM (T EMRA ) are associated with responses against infections and graft-versus-leukemia (GVL) effect [13, 18–21]. In patients, we and others demonstrated that a high proportion of CCR7 + donor T-cell These authors contributed equally: Carlos Cuesta-Mateos, Itxaso Portero-Sainz * Cecilia Muñoz-Calleja cmunozc@salud.madrid.org 1 Department of Immunology, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de La Princesa, Madrid, Spain 2 Immunological and Medicinal Products S.L. (IMMED), Madrid, Spain 3 Centro de Biología Molecular Severo Ochoa (CBM-SO), Madrid, Spain 4 Methodology Unit, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de La Princesa, Madrid, Spain 5 Department of Microbiology, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de La Princesa, Madrid, Spain 6 Department of Hematology, Instituto de Investigación Sanitaria Princesa, Hospital Universitario de La Princesa, Madrid, Spain Supplementary information The online version of this article (https:// doi.org/10.1038/s41409-020-0830-8) contains supplementary material, which is available to authorized users. 1234567890();,: 1234567890();,: