Jw. Won et al., Tumorigenicity of mouse thymoma is suppressed by soluble type II transforming growth factor beta receptor therapy, CANCER RES, 59(6), 1999, pp. 1273-1277
Many types of tumor cells overexpress transforming growth factor beta (TGF-
beta), which is believed to promote tumor progression. We hypothesized that
overexpression of the extracellular region of the type II TGF-beta recepto
r (soluble T beta RII) would compete for or block TGF-beta binding to T bet
a Rs on immune cells, preventing TGF-beta-mediated immunosuppression and co
nsequently resulting in the eradication of tumor cells, We tested this in t
he mouse thymoma cell line EL4, which has been reported to suppress cellula
r immunity by secreting a large amount of TGF-beta, Transduction of EL4 wit
h recombinant retrovirus encoding soluble T beta RII resulted in the secret
ion of heterogeneously glycosylated, 25 to 35 kDa truncated T beta RII, Ino
culation of 1 x 10(4) to 5 x 10(4) soluble T beta RII-modified EL4 cells (E
L4/Ts, EL4 cells transduced with recombinant retrovirus encoding soluble T
beta RII and neomycin resistance gene) s.c. to mice showed reduced tumorige
nicity, as indicated by Lower overall tumor incidence (7%, 1 of 14; P < 0.0
01) compared with unmodified EL4 (100%, 9 of 9) or vector-modified EL4 cell
s (EL4/neo, EL4 cells transduced with recombinant retrovirus encoding neomy
cin resistance gene; 100%, 4 of 4), Administration of mitomycin C-treated E
L4/Ts cells (1 x 10(6)) after EL4 inoculation (1 x 104) reduced tumor incid
ence from 100% (5 of 5 in mice inoculated with mitomycin C-treated EL4/neo)
to 40% (4 of 10, P < 0.05), indicating that supply of soluble T beta RII c
ould actually block TGF-beta-mediated tumorigenesis. In vitro tumor cytotox
icity assays revealed 3-5-fold higher cytotoxic activity with lymphocytes f
rom EL4/Ts-bearing mice compared with those from EL4- or EL4/neo-bearing mi
ce, indicating that the observed tumor rejection was mediated by restoratio
n of the tumor-specific cellular immunity. These data suggest that expressi
on of soluble T beta RII is an effective strategy for treating highly progr
essive tumors secreting TGF-beta.