RESUMEN
To date, chronic lymphocytic leukemia (CLL) remains incurable with current treatments, which include the monoclonal antibodies (mAbs) rituximab and alemtuzumab. The efficacy of rituximab is modest when used as single agent, and alemtuzumab induces severe immunosuppression. To develop more potent and specific therapies, we propose the CC chemokine receptor 7 (CCR7) as an attractive target molecule to treat CLL, as it not only fulfills the requirements of a high-surface expression and a good level of tissue specificity, but it also plays a crucial role in mediating the migration of the tumor cells to lymph nodes (LNs) and thus, in the development of clinical lymphadenopathy. In the current work, murine anti-human CCR7 mAb mediated a potent, complement-dependent cytotoxicity (CDC) against CLL cells while sparing normal T lymphocytes from the same patients. The sensitivity to CDC was related to the antigenic density of CCR7. Moreover, these mAb blocked the in vitro migration of CLL cells in response to CC chemokine ligand 19 (CCL19), one of the physiological ligands of CCR7. Conversely, CLL cells were poorly lysed through antibody-dependent, cell-mediated cytotoxicity (ADCC), probably as a result of the murine origin and the isotype of the anti-CCR7 mAb used. Molecular engineering techniques will allow us to obtain chimeric or humanized anti-CCR7 mAb to reach the best clinical response for this common and yet incurable leukemia.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/inmunología , Leucemia Linfocítica Crónica de Células B/patología , Receptores de Quimiocina/antagonistas & inhibidores , Anciano , Anciano de 80 o más Años , Animales , Anticuerpos Monoclonales/inmunología , Especificidad de Anticuerpos , Citotoxicidad Celular Dependiente de Anticuerpos , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , División Celular/efectos de los fármacos , División Celular/inmunología , Línea Celular Tumoral/inmunología , Línea Celular Tumoral/patología , Quimiocina CCL19 , Quimiocinas CC/farmacología , Quimiotaxis de Leucocito/efectos de los fármacos , Quimiotaxis de Leucocito/inmunología , Citotoxicidad Inmunológica , Ensayos de Selección de Medicamentos Antitumorales , Endocitosis , Femenino , Humanos , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/terapia , Masculino , Ratones , Persona de Mediana Edad , Receptores CCR7 , Receptores de Quimiocina/inmunología , Especificidad de la Especie , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
B cell neoplasms present heterogeneous patterns of lymphoid organ involvement, which may be a result of the differential expression of chemokine receptors. We found that chemokine receptor (CCR)7, CXC chemokine receptor (CXCR)4, or CXCR5, the main chemokine receptors that mediate B cell entry into secondary lymphoid tissues and their homing to T cell and B cell zones therein, were highly expressed in B malignancies with widespread involvement of lymph nodes. Conversely, those pathologies with little or no nodular dissemination showed no expression to very low levels of CCR7 and CXCR5 and low to moderate levels of CXCR4. These findings provide evidence for the role of CCR7, CXCR4, and CXCR5 in determining the pattern of lymphoid organ involvement of B tumors. Functional studies were performed on B malignancies expressing different levels of CCR7, CXCR5, and CXCR4. Multiple myeloma (MM) cells did not express CCR7 nor CXCR5 and did not migrate in response to their ligands; a moderate expression of CXCR4 on MM cells was accompanied by a migratory response to its ligand, CXCL12. By contrast, cells from B cell chronic lymphocytic leukemia (B-CLL) expressed the highest levels of these chemokine receptors and efficiently migrated in response to all ligands of CCR7, CXCR4, and CXCR5. In addition, the migration index of B-CLL cells in response to both of the CCR7 ligands correlated with the presence of clinical lymphadenopathy, thus indicating that the high expression of functional chemokine receptors justifies the widespread character of B-CLL, representing a clinical target for the control of tumor cell dissemination.