ANTITUMOR PROTECTION FROM THE MURINE T-CELL LEUKEMIA-LYMPHOMA EL4 BY THE CONTINUOUS SUBCUTANEOUS COADMINISTRATION OF RECOMBINANT MACROPHAGE-COLONY-STIMULATING FACTOR AND INTERLEUKIN-2

Citation
Da. Vallera et al., ANTITUMOR PROTECTION FROM THE MURINE T-CELL LEUKEMIA-LYMPHOMA EL4 BY THE CONTINUOUS SUBCUTANEOUS COADMINISTRATION OF RECOMBINANT MACROPHAGE-COLONY-STIMULATING FACTOR AND INTERLEUKIN-2, Cancer research, 53(18), 1993, pp. 4273-4280
Citations number
61
Categorie Soggetti
Oncology
Journal title
ISSN journal
00085472
Volume
53
Issue
18
Year of publication
1993
Pages
4273 - 4280
Database
ISI
SICI code
0008-5472(1993)53:18<4273:APFTMT>2.0.ZU;2-I
Abstract
Combined continuous s.c. coadministration of macrophage-colony stimula ting factor (M-CSF) plus interleukin-2 (IL-2) by osmotic pump protecte d mice given i.v. injections of a lethal dose of EL4 T-cell leukemia/l ymphoma. Antitumor protection was significantly greater than that affo rded by treatment with either cytokine alone. Since neither IL-2 recep tors nor M-CSF receptors were expressed on EL4, the antitumor effect w as likely attributed to murine effector cells. To determine how M-CSF + IL-2 provided this effect, we performed immunophenotypic and functio nal analyses as well as in vivo depletion studies of putative antitumo r effector cells. Splenic phenotyping experiments revealed that the hi ghest levels of macrophages and natural killer cells were observed in mice given the cytokine combination rather than either M-CSF or IL-2 a lone. In vivo depletion of natural killer cells ablated the antitumor protective effect of M-CSF and IL-2. T-cells were also important for M -CSF + IL-2 efficacy, since adult thymectomy/T-cell depletion signific antly inhibited the ability of cytokine coadministration to protect ag ainst EL4. Coadministration of the 2 cytokines significantly elevated in vivo levels of CD3+CD4+, CD3+CD8+, CD3+NK1.1+ T-cells, and CD3+CD25 + (activated) T-cells, and elevated anti-EL4 cytotoxic T-cell activity measured in vitro. Although WBC counts and fluorescence-activated cel l sorter studies showed that M-CSF + IL-2 treatment significantly elev ated neutrophils, s.c. delivery of granulocyte-colony stimulating fact or at doses sufficient to induce neutrophilia was unable to confer ant i-EL4 protection. These studies indicate that macrophages, T-cells, an d natural killer cells are all important in the M-CSF + IL-2 anti-EL4 response. The superior antitumor effect of this cytokine combination a long with the ability of M-CSF to diminish the toxicity of IL-2 in thi s model suggests that further investigations into the clinical potenti al of this combination treatment are warranted.