Effective TRAIL-based immunotherapy requires both plasmacytoid and CD8α dendritic cells.
It is now appreciated that there are distinct subsets of dendritic cells (DC) with specialized functions. Plasmacytoid DC (pDC) and CD8α DC can contribute to the priming, activation and function of antitumor CD8 T cells; however, their specific roles and necessity in stimulating antitumor immunity are not clearly understood. We examined the importance of pDC and CD8α DC during immunotherapy of an orthotopic model of metastatic renal cell carcinoma. Immunotherapy that utilizes a recombinant adenovirus encoding tumor necrosis factor-related apoptosis-inducing ligand (Ad5-TRAIL) in combination with an immunostimulatory CpG-containing oligodeoxynucleotide (CpG) resulted in the clearance of primary and metastatic tumors in wild-type (WT) replete BALB/c mice and prolonged survival. In comparison, mice deficient in either pDC (accomplished using a depleting mAb specific for PDCA1) or CD8α DC (through utilization of CD8α DC-deficient Batf3(-/-) BALB/c mice) had uncontrolled tumor growth and high mortality after Ad5-TRAIL/CpG administration. The ineffectiveness of Ad5-TRAIL/CpG therapy in the anti-PDCA1-treated and Batf3(-/-) BALB/c mice was marked by an altered activation phenotype of the DC, as well as significantly reduced expression of type I IFN-stimulated genes and IL-15/IL-15R complex production. In addition, pDC-depleted and Batf3(-/-) BALB/c mice had significantly decreased effector CD8 T cell infiltration in the primary tumor site compared with WT mice after therapy. These data collectively suggest that pDC and CD8α DC carry out independent, but complementary, roles that are necessary to initiate an efficacious antitumor immune response after Ad5-TRAIL/CpG therapy.
Department of Urology, University of Minnesota, 3-125 CCRB, 2231 6th St. SE, Minneapolis, MN, 55455, USA.
Britnie R
BR
James
Erik L
EL
Brincks
Tamara A
TA
Kucaba
Louis
L
Boon
Thomas S
TS
Griffith
D000818:Animals; D016827:CD8 Antigens / Q000276:immunology*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005260:Female; D007167:Immunotherapy / Q000379:methods*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*
D016827:CD8 Antigens; C409469:CD8 antigen, alpha chain; D053221:TNF-Related Apoptosis-Inducing Ligand