Combination of gamma-irradiation and dendritic cell administration induces a potent antitumor response in tumor-bearing mice: approach to treatment of advanced stage cancer.
We investigated a new approach to the treatment of advanced stage cancer, a combination of apoptosis-inducing therapy and dendritic cell (DC) administration. MethA sarcoma and C3 tumor containing defined tumor-specific antigens in form of peptides' epitopes were selected as experimental mouse models. Sites of established subcutaneous tumors were gamma-irradiated with 10 Gy 3-5 times with 4-5 day interval. DCs generated from bone marrow of syngeneic mice were injected i.v. and s.c. after each irradiation. A large number of cell tracker-labeled DCs accumulated at the site of the irradiated tumor after s.c. injections. This effect was not observed in non-irradiated tumors. Almost all of these DCs bound GFP-labeled MethA cells in tumor tissue. Interferon-gamma production by splenocytes in response to the tumor-specific MHC class I matched peptides was determined by ELISPOT assays. The combination of gamma-irradiation and DC administration, but not each of the treatments alone resulted in a significant increase in T cell response to the specific, but not to the control peptides. An increased proportion of tumor peptide-specific CD8(+)-cells was found only in that group of mice using staining with tetramers. DCs with defective presentation of antigen via MHC class I or MHC class II pathways were unable to induce peptide-specific T cell response. The combination of gamma-irradiation and DC administration but not each of the treatments alone resulted in a dramatic antitumor effect. A substantial proportion of mice completely rejected their tumors (80% in case of MethA sarcoma and 40% in case of C3 tumor). In the rest of the mice, tumor growth was notably suppressed or completely blocked. These data suggest that the combination of apoptosis-inducing therapy and DC administration may be an attractive approach to the treatment of advanced cancer.
Nikitina
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H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL 33612, USA.
Gabrilovich
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D000818:Animals; D017951:Antigen Presentation; D017209:Apoptosis; D003131:Combined Modality Therapy; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D005720:Gamma Rays; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*
D007371:Interferon-gamma