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