Combined interleukin 1/interleukin 2 therapy of mice injected with highly metastatic Friend leukemia cells: host antitumor mechanisms and marked effects on established metastases.
Peritumoral injection of recombinant human interleukin 1 beta (IL-1 beta) in mice transplanted subcutaneously with Friend erythroleukemia cells (FLC) resulted in a marked increase in survival time and inhibition of metastatic tumor growth in liver and spleen. In contract, IL-2 treatment alone did not significantly inhibit the development of FLC metastases. A synergistic antitumor effect was observed after combined IL-1/IL-2 therapy of these mice. The antitumor action of IL-1/IL-2 treatment was abolished or markedly reduced in mice treated with antibodies to CD4 or CD8 antigens, whereas antibodies to asialo-GM1 were ineffective. A clear-cut increase in the percentage of CD4+ cells was observed in the spleens of cytokine-treated mice on days 17 and 23. On day 23 of cytokine therapy, CD8+ cells were increased in both spleens and lymph nodes. On day 17, infiltrates of host-reactive cells (i.e., lymphocytes, granulocytes, and monocytes) were observed in both spleen and liver from FLC-injected mice treated with IL-1/IL-2, in association with tumor cells. On days 17 and 23, spleen cells and cells recovered from mesenteric lymph nodes of IL-1/IL-2-treated mice exerted a potent antitumor effect as determined by Winn assay experiments. This antitumor activity was abolished by preincubation of spleen cells with anti-CD8 antibody, but not by treatment with antibodies to asialo-GM1; antibodies to CD4 exerted only a slight effect. Combined IL-1/IL-2 therapy was more effective on established (i.e., 6-7-d) FLC tumors than on early (i.e., 1-d) tumor-transplanted mice. IL-1/IL-2 treatments were also highly effective in increasing survival time of mice from which the subcutaneous primary tumors were excised 7 d after FLC injection. These data indicate that in mice injected with FLC, the antitumor effects of IL-1/IL-2 are mediated by CD4+ and CD8+ cells (but not NK cells), and suggest that this combined cytokine treatment may be effective against established metastatic tumors.
Ciolli
V
V
Department of Virology, Istituto Superiore di Sanità, Rome, Italy.
Gabriele
L
L
Sestili
P
P
Varano
F
F
Proietti
E
E
Gresser
I
I
Testa
U
U
Montesoro
E
E
Bulgarini
D
D
Mariani
G
G
D000818:Animals; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D004338:Drug Combinations; D004357:Drug Synergism; D005434:Flow Cytometry; D007375:Interleukin-1 / Q000008:administration & dosage; D007376:Interleukin-2 / Q000008:administration & dosage; D004915:Leukemia, Erythroblastic, Acute / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000627:therapeutic use; D013160:Splenic Neoplasms / Q000517:prevention & control / Q000556:secondary; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
D000911:Antibodies, Monoclonal; D004338:Drug Combinations; D007375:Interleukin-1; D007376:Interleukin-2; D011994:Recombinant Proteins