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

166 8 Interleukin-10 in Cancer Immunity
angiogenesis and metastasis. More importantly, none of the mice bearing TGF-b-expressing
tumor cells survived compared to 80 % of those expressing IL-10 [129]. IL-
10 can inhibit the angiogenesis also by inhibiting tumor-resident macrophages. Bar-
Eli et al. reported that the transplantation of human melanoma cells that had been
transfected with the murine IL-10 cDNA into nude mice resulted in fewer lung metastases
and significant inhibition of tumor growth. The authors suggested that this
was due to inhibition of angiogenesis by IL-10. They referred to the fact that IL-10
down-regulated the production of vascular endothelial growth factor in the tumor-associated
macrophages. Other factors involved in neovascularization such as IL-1b,
TNF-a and IL-6 were also inhibited [130, 131].
Different groups described the positive effect of IL-10 on NK cell activity resulting in
an indirect negative effect on cancer growth. NK cell activity is especially important
in cases of diminished MHC class I expression by the tumor cells. Low MHC class I
expression can be the normal feature of this cell type, but might also be induced by
immune mediators like IL-10. Velu et al. demonstrated a loss of tumorigenicity of
melanoma cells injected into syngeneic mice after previous retroviral transfection of
these cells with IL-10 cDNA. Host T cells and NK cells might be involved in the observed
tumor eradication because IL-10-producing tumor cells grew in nude mice
and in CD8 + T or NK cell-depleted mice [132]. Similar observations have been reported
by Fulton's group. They described that injection of the murine mammary tumor
cell line 410.4 in syngeneic mice resulted in progressive growth and death from
pulmonary metastases. In contrast, transfection of IL-10 cDNA in these cell lines resulted
in complete inhibition of growth and metastatic disease. Interestingly, the
antimetastatic activity of IL-10 is expressed in T cell-deficient mice but is lost when
NK cell activity is suppressed. These authors also point out the importance of IL-10mediated
reduction of MHC class I expression by tumor cells [133].
8.6
Conclusions
Various tumors are associated with locally, and upon tumor progression also systemically,
elevated IL-10 levels. IL-10 was found to be produced by both the tumor
cells as well as immune cells. Elevated IL-10 serum levels are associated with a
poor prognosis. Several experimental investigations pointed to opposite directions
regarding the influence of IL-10 on the cancer ± either to favor or to inhibit the existence
and progression of tumors. In summary, it remains difficult to give a clear
postulate concerning the role of IL-10 in tumor development as it induces numerous
and contrary effects. Whether it will act as an inhibitor or stimulator of the tumor
may depend on different factors such as the species of tumor and the stage of
disease. Three questions appear to be especially important in context of the species
of tumor:
1. Does IL-10 directly modulate the proliferation of the tumor cells?
2. Is the neovascularization essential for the progression of the tumor?