Combined treatment with dendritic cells and 5-fluorouracil elicits augmented NK cell-mediated antitumor activity through the tumor necrosis factor-alpha pathway.
Antitumor effects and mechanism of combined therapy with a dendritic cell (DC) vaccine and fluorouracil (5-FU) were investigated. Cytotoxic activity against MC38 cells, untreated or pretreated with 5-FU, was examined in splenocytes from mice inoculated with DCs: DCs pulsed with MC38 lysate or treated with LPS or both and untreated DCs. Inoculation with all types of DCs induced the significant cytotoxic activity of splenocytes, and pretreatment of MC38 cells with 5-FU significantly enhanced the cytotoxic activity of splenocytes. Depletion of natural killer (NK) cells, but not of CD8 or CD4 T cells, in the splenocytes from DC (without MC38 lysate-pulse or LPS treatment thereafter)-inoculated mice decreased the cytotoxic activity. The cytotoxic effect was eliminated by treatment with a monoclonal antibody (mAb) against tumor necrosis factor (TNF)-alpha and was partially inhibited by concanamycin A. Inoculation of mice with DCs upregulated TNFalpha expression on NK cells. MC38 cells pretreated with 5-FU exhibited enhanced expression of procaspase 8 and efficiently underwent apoptosis by TNF-alpha with activation of caspase 8. Although treatment with 5-FU upregulated Rae-1 expression on MC38 cells, the NK-cell-mediated cytotoxic activity was not suppressed by treatment with an anti-Rae-1 mAb or an antinatural killer group 2D mAb or both. These results indicate that combined therapy with a DC vaccine and 5-FU is a promising strategy for cancer treatment mediated by the tumoricidal activity of NK cells through the TNF-alpha pathway.
Nagasaki
Eijiro
E
*Department of Oncology, Institute of DNA Medicine daggerDivision of Oncology and Hematology double daggerDivision of Gastroenterology and Hepatology, Department of Internal Medicine section signInstitute of Clinical Medicine and Research, The Jikei University School of Medicine parallelDepartment of Immunology, Juntendo University School of Medicine, Tokyo, Japan.
Takahara
Akitaka
A
Koido
Shigeo
S
Sagawa
Yukiko
Y
Aiba
Keisuke
K
Tajiri
Hisao
H
Yagita
Hideo
H
Homma
Sadamu
S
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines; D002457:Cell Extracts / Q000276:immunology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D013154:Spleen / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D019138:Antibodies, Blocking; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D002457:Cell Extracts; D014409:Tumor Necrosis Factor-alpha; D005472:Fluorouracil