Ectopic expression of CCL19 impairs alloimmune response in mice.
Initiation of an antitumour immune response is characterized by a complex process of chemokine-mediated cell migration and cell-cell interactions. Overexpression of chemokine CCL19 in tumour cells has been shown to result in accelerated tumour rejection under certain experimental conditions, suggesting a novel approach in the therapy of neoplastic malignancies. To investigate CCL19-mediated modulations of cellular immune responses in vivo, we generated a chimeric CCL19-immunoglobulin G2b (IgG2b) Fc fusion protein, which binds to the chemokine receptor CCR7 comparable to native CCL19. CCL19-IgG2b possesses a long-lasting potent chemotactic activity as a result of the extended half-life of Fc fusion proteins. Stable overexpression of CCL19-IgG2b in BALB/c-derived J558L tumour cells fails to support tumour cell rejection following transplantation in syngeneic mice. Moreover, overexpression of CCL19-IgG2b hinders tumour rejection in allogeneic C57BL/6 mice. This phenomenon was accompanied by a six-fold increase of dendritic cells (DCs) isolated from CCL19-IgG2b-secreting tumours when compared to the number of DCs isolated from control parental J558L tumours. While mice bearing the allogeneic parental tumour showed an intense hypercellularity in the draining lymph nodes, no such response could be observed in the draining lymph nodes of mice carrying the CCL19-IgG2b-secreting tumour. We could demonstrate that overexpression of CCL19-IgG2b in tumour cells retains antigen-presenting cells in the tumour mass and prevents DCs from migrating into draining lymph nodes to present antigens and to activate T cells, resulting in an impaired immune response against the tumour.
Krautwald
Stefan
S
Department of Nephrology and Hypertension, University of Schleswig-Holstein, Campus Kiel, Germany.
Ziegler
Ekkehard
E
Förster
Reinhold
R
Ohl
Lars
L
Amann
Kerstin
K
Kunzendorf
Ulrich
U
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D054415:Chemokine CCL19; D019742:Chemokines, CC / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000276:immunology; D007108:Immune Tolerance; D007074:Immunoglobulin G / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000276:immunology* / Q000473:pathology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology; D014407:Tumor Cells, Cultured
C515461:Ccl19 protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D019742:Chemokines, CC; D007074:Immunoglobulin G; D007519:Isoantigens; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D011993:Recombinant Fusion Proteins