Synergistic anti-tumor responses after administration of agonistic antibodies to CD40 and IL-2: coordination of dendritic and CD8+ cell responses.
In cancer, the coordinate engagement of professional APC and Ag-specific cell-mediated effector cells may be vital for the induction of effective antitumor responses. We speculated that the enhanced differentiation and function of dendritic cells through CD40 engagement combined with IL-2 administration to stimulate T cell expansion would act coordinately to enhance the adaptive immune response against cancer. In mice bearing orthotopic metastatic renal cell carcinoma, only the combination of an agonist Ab to CD40 and IL-2, but neither agent administered alone, induced complete regression of metastatic tumor and specific immunity to subsequent rechallenge in the majority of treated mice. The combination of anti-CD40 and IL-2 resulted in significant increases in dendritic cell and CD8(+) T cell number in advanced tumor-bearing mice compared with either agent administered singly. The antitumor effects of anti-CD40 and IL-2 were found to be dependent on CD8(+) T cells, IFN-gamma, IL-12 p40, and Fas ligand. CD40 stimulation and IL-2 may therefore be of use to promote antitumor responses in advanced metastatic cancer.
Murphy
William J
WJ
Department of Microbiology, University of Nevada School of Medicine, Reno, NV 89557, USA. wmurphy@unr.edu
Welniak
Lisbeth
L
Back
Timothy
T
Hixon
Julie
J
Subleski
Jeff
J
Seki
Naoko
N
Wigginton
Jon M
JM
Wilson
Susan E
SE
Blazar
Bruce R
BR
Malyguine
Anatoli M
AM
Sayers
Thomas J
TJ
Wiltrout
Robert H
RH
D000230:Adenocarcinoma / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D019013:CD40 Antigens / Q000096:biosynthesis / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018827:Carcinoma, Lewis Lung; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D002450:Cell Communication / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D004357:Drug Synergism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D007376:Interleukin-2 / Q000008:administration & dosage*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009368:Neoplasm Transplantation; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D019013:CD40 Antigens; D018984:Epitopes, T-Lymphocyte; D007106:Immune Sera; D007376:Interleukin-2