Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

of DCs (see above). In line with this, Strieter's group reported that PBMC cultured
with supernatants from human bronchogenic cell lines only in the presence of anti-
IL-10 antibodies increased their TNF-a and IL-6 production [83]. As mentioned
above, cutaneous carcinoma produces IL-10. T cells lines established from tumor-infiltrating
lymphocytes proliferated in the presence of autologous tumor cells dependent
on the addition of anti-IL-10 antibodies [84]. Similar results were reported for
the newly identified subset of monocytes from malignant ascites of patients with
ovarian carcinoma. These monocytes inhibited the proliferation of autologous T cells
in response to phytohemagglutinin. Moreover, this inhibition could be reversed by
addition of anti-IL-10 and anti-TGF-b antibodies [94]. The consequence of IL-10 presence
and thereby inhibition of the antitumor immune reaction might be the uncontrolled
development of cancers. This has been demonstrated in transgenic mice expressing
IL-10 under the control of the IL-2 promoter. These animals are unable to
limit the growth of immunogenic tumors. However, administration of anti-IL-10
antibodies restored the anticancer response [123]. Not surprisingly, these mice show
defects not only in T cells but also in APC. The latter have suppressed capacity to
produce IL-12 production and to induce a T cell reaction [124].
These examples show that IL-10 is able to favor tumor growth both directly by affecting
the tumor cells and indirectly by affecting the immune cells.
8.5.2
Tumor-Inhibiting Effectsof IL-10
8.5 Effects of IL-10 in Cancer Models
IL-10 can directly exert a negative effect on tumor cells. For instance, it inhibits the
spontaneous proliferation of acute myelogenous leukemia blast cells. This is an irreversible
inhibitory effect as inhibition could also be demonstrated when the cytokine
was present only at the beginning of culture. However, independently on the effect
on proliferation, IL-10 reduces IL-1a/b, TNF-a, GM-CSF and IL-6 secretion by these
cells [125]. Similar effects are seen on chronic myelomonocytic leukemia cells. IL-10
dose-dependently inhibits the growth of these cells. This is due to a decrease of GM-
CSF mRNA and protein [126]. Another direct negative effect of IL-10 on tumor survival
has been described by Fulton's group. They observed that IL-10 gene transfer in
murine mammalian tumor cells was associated with increased expression of the inducible
isoform of NO synthase (iNOS). The activity of this enzyme was elevated as
well. This can result in elevated levels of NO in transfected tumor cells [127]. NO is
known to have potent antitumor activity.
IL-10 can inhibit the generation of new vessels within the tumor both directly by acting
on the tumor cells and indirectly by influencing infiltrating immune cells. IL-10
induced the tissue inhibitor of metalloproteinase (TIMP)-2 in primary human prostate
cancer cells. Simultaneously, it reduced the secretion of matrix metalloproteinase
(MMP)-2 and -9 from these cells. The consequence was the inhibition of microvessel
formation [128]. Interestingly, TGF-b induced the expression of MMP-2 and
this induction was prevented by IL-10. When primary human prostate cancer cells
either expressing TGF-b or IL-10 were implanted in SCID mice, TGF-b promoted tumor
growth, angiogenesis and metastasis. In contrast, IL-10 reduced growth rates,
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