In vivo depletion of DC impairs the anti-tumor effect of agonistic anti-CD137 mAb.
Anti-CD137 mAb are capable of inducing tumor rejection in several syngeneic murine tumor models and are undergoing clinical trials for cancer. The anti-tumor effect involves co-stimulation of tumor-specific CD8(+) T cells. Whether antigen cross-presenting DC are required for the efficacy of anti-CD137 mAb treatment has never been examined. Here we show that the administration of anti-CD137 mAb eradicates EG7-OVA tumors by a strictly CD8beta(+) T-cell-dependent mechanism that correlates with increased CTL activity. Ex vivo analyses to determine the identity of the draining lymph node cell type responsible for tumor antigen cross-presentation revealed that CD11c(+) cells, most likely DC, are the main players in this tumor model. A minute number of tumor cells, revealed by the presence of OVA cDNA, reach tumor-draining lymph nodes. Direct antigen presentation by tumor cells themselves also participates in anti-OVA CTL induction. Using CD11c diphtheria toxin receptor-green fluorescent protein-->C57BL/6 BM chimeric mice, which allow for sustained ablation of DC with diphtheria toxin, we confirmed the involvement of DC in tumor antigen cross-presentation in CTL induction against OVA(257-264) epitope and in the antitumor efficacy induced by anti-CD137 mAb.
Murillo
Oihana
O
Gene Therapy Unit, Centro de Investigación Médica Aplicada, Universidad de Navarra, Pamplona, Spain.
Dubrot
Juan
J
Palazón
Asís
A
Arina
Ainhoa
A
Azpilikueta
Arantza
A
Alfaro
Carlos
C
Solano
Sarai
S
Ochoa
María C
MC
Berasain
Carmen
C
Gabari
Izaskun
I
Pérez-Gracia
José L
JL
Berraondo
Pedro
P
Hervás-Stubbs
Sandra
S
Melero
Ignacio
I
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017951:Antigen Presentation / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D045744:Cell Line, Tumor; D045142:Cross-Priming / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000819:agonists* / Q000276:immunology
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; C110366:OVA-8; D010446:Peptide Fragments; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D010047:Ovalbumin