Compromised anti-tumor responses in tumor necrosis factor-alpha knockout mice.
The response of lymphokine-activated killer (LAK) and natural killer (NK) cells from mice lacking tumor necrosis factor-alpha (TNF-alpha-/- mice) was impaired in cytotoxicity assays against various tumor cell targets. Furthermore, allogeneic cytotoxic T lymphocyte (CTL) responses were also impaired as compared to TNF-alpha+/+ littermates (control mice). Cytotoxicity was restored both upon in vitro incubation of TNF-alpha-/- lymphocytes with recombinant TNF-alpha (rTNF-alpha) or upon in vivo treatment of TNF-alpha-/- mice with rTNF-alpha. Using combinations of monoclonal antibodies we were able to show that TNF-alpha-/- effector lymphocytes exhibit both perforin- and Fas ligand-based cytotoxicity. Furthermore, upon in vivo administration of rTNF-alpha these effectors, in addition to perforin and Fas ligand, are also armed with TNF-alpha cytotoxic molecules, thus resembling to the cytotoxic effectors from control mice. In a tumor model, immunized TNF-alpha-/- mice failed to reject the syngeneic fibrosarcoma MC57X, but did so when injected with rTNF-alpha. In vivo administration of anti-TNF-alpha mAb neutralized the effect of rTNF-alpha supporting the growth of MC57X cells. Our data provide novel evidence for TNF-alpha as an essential factor in (i) controlling cytotoxicity in vitro and in vivo and (ii) promoting tumor rejection in vivo.
Cancer Immunology and Immunotherapy Center, St. Savas Cancer Hospital, Athens, Greece.
C N
CN
Baxevanis
I F
IF
Voutsas
O E
OE
Tsitsilonis
M L
ML
Tsiatas
A D
AD
Gritzapis
M
M
Papamichail
D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D005354:Fibrosarcoma / Q000276:immunology*; D015979:Killer Cells, Lymphokine-Activated / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000276:immunology; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology* / Q000494:pharmacology
D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha