Abstract
BackgroundThe chemokine receptor CCR7 mediates lymphoid dissemination of many cancers, including lymphomas and epithelial carcinomas, thus representing an attractive therapeutic target. Previous results have highlighted the potential of the anti-CCR7 monoclonal antibodies to inhibit migration in transwell assays. The present study aimed to evaluate the in vivo therapeutic efficacy of an anti-CCR7 antibody in a xenografted human mantle cell lymphoma model.MethodsNOD/SCID mice were either subcutaneously or intravenously inoculated with Granta-519 cells, a human cell line derived from a leukemic mantle cell lymphoma. The anti-CCR7 mAb treatment (3 × 200 μg) was started on day 2 or 7 to target lymphoma cells in either a peri-implantation or a post-implantation stage, respectively.ResultsThe anti-CCR7 therapy significantly delayed the tumor appearance and also reduced the volumes of tumors in the subcutaneous model. Moreover, an increased number of apoptotic tumor cells was detected in mice treated with the anti-CCR7 mAb compared to the untreated animals. In addition, significantly reduced number of Granta-519 cells migrated from subcutaneous tumors to distant lymphoid organs, such as bone marrow and spleen in the anti-CCR7 treated mice. In the intravenous models, the anti-CCR7 mAb drastically increased survival of the mice. Accordingly, dissemination and infiltration of tumor cells in lymphoid and non-lymphoid organs, including lungs and central nervous system, was almost abrogated.ConclusionsThe anti-CCR7 mAb exerts a potent anti-tumor activity and might represent an interesting therapeutic alternative to conventional therapies.
Highlights
The chemokine receptor CCchemokine receptor 7 (CCR7) mediates lymphoid dissemination of many cancers, including lymphomas and epithelial carcinomas, representing an attractive therapeutic target
The dissemination of lymphomas does not always reflect the progression of the tumor, but recapitulates the so-called homing signature of normal lymphoid cells, which is characterized by a conserved pattern of migration and recirculation [1,2]
CCchemokine receptor 7 (CCR7) is a well-characterized chemokine receptor that is expressed on naïve and central memory lymphocytes and mature dendritic cells and this allows these cells to respond to the ligands of CCR7, the homeostatic chemokines CC-chemokine ligand 21 (CCL21) and CCL19, produced in secondary lymphoid organs (SLO) [9]
Summary
The chemokine receptor CCR7 mediates lymphoid dissemination of many cancers, including lymphomas and epithelial carcinomas, representing an attractive therapeutic target. The dissemination of lymphomas does not always reflect the progression of the tumor, but recapitulates the so-called homing signature of normal lymphoid cells, which is characterized by a conserved pattern of migration and recirculation [1,2] This particular tissue tropism explains the rapid dissemination of lymphomas and the different patterns of tissue infiltration of the Homing of normal lymphoid cells is a multistep process that requires chemotaxis, cell adhesion, and extravasation of lymphocytes across the vessel wall. CCR7 is required for the entry of normal T and B lymphocytes through the endothelium of high endothelial venules into the SLO, including lymph nodes and Peyer’s patches [10,11] Consistent with their lymphoid origin, many leukemias and lymphomas express CCR7 [12,13,14,15,16]. CCR7 has been implicated in acute T-cell leukemia infiltration of the central nervous system (CNS) [18]
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