Función de CCR5 y sus ligandos en la respuesta del sistema inmune adaptativo frente a tumores

Tesis doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 20-07-2009The chemokine receptor CCR5 and its ligands have been implicated in tumor pathogenesis although it is unclear whether they promote or restrict cancer progression. Our aim is to determine the role of CCR5 in controlling tumor progression, focusing specially on the function of this receptor in the T cell response to the tumor. To address this issue, we analyzed the in vivo contribution of CCR5 to cancer in four different animal models. In a first approach, we modulated the levels of CCR5 ligands secreted by tumor cells injected subcutaneously into syngeneic CCR5 KO or wild-type mice. Stable silencing or overexpression of CCR5 agonists resulted in an enhanced or reduced tumor growth rate, respectively, compared to mock cells expressing low amounts of CCR5 ligands. This effect was observed when syngeneic tumors were injected into CCR5-expressing mice, but not in CCR5 KO and RAG-2 immunodeficient mice. We also observed subtle CCL5/CCR5 expression-dependent changes in leukocyte infiltration of tumors. To further analyze CCR5 function in the T cell-mediated immune response to tumor antigens, we generated OVA-specific, TCR transgenic CD8 and CD4 cells (OT1/OT2), that did or did not express CCR5. Our data demonstrate that CCR5 expression in both CD8 and CD4 antigen-specific T cells is necessary for effective rejection of subcutaneously-transplanted, OVA-expressing tumors. Analysis of T cell proliferation, activation and migration revealed the importance of CCR5 in CD8 T cell infiltration into the tumor parenchyma. Finally, we assessed the CCR5 contribution to tumor onset and development in two models of tumorigenesis: the transgenic MMTV-Her2/neu mouse model, which generates spontaneous mammary tumors at 8-9 months of age, and the methylcholantrene (MCA)-induced fibrosarcoma model. Onset, incidence and growth of MCA-induced fibrosarcomas were significantly decreased in CCR5 WT compared to CCR5 KO mice. We also found differences in the onset and incidence of the mammary tumors in FVB-C57BL/6 MMTVneu mice bearing a single transgene copy; these differences were lost in FVB-C57BL/6 MMTVneu mice with two transgene copies or when backcrossed into a FVB background. Our results suggest that CCR5 has an important role in tumor immunosurveillance in specific circumstances, which most likely favors a cooperative tumor-specific response by CD4 and CD8 T cells