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

164 8 Interleukin-10 in Cancer Immunity
be made in patients with cutaneous T cell lymphoma (mucosis fungoides). Mucosis
fungoides progression was associated with significantly higher IL-10 and lower IFNg
mRNA expression in skin lesions [97].
Elevated IL-10 serum levels have been described as a negative prognostic factor for
responsiveness towards treatment, and disease-free and overall survival by patients
with melanoma and solid tumors, particularly with lung and gastrointestinal cancer.
Moreover, a further significant increase in IL-10 serum levels has been observed in
non-responders after chemotherapy [115, 110±113]. Tumor resection resulted in a decrease
in IL-10 levels [114].
8.5
Effectsof IL-10 in Cancer Models
Several experimental investigations has been performed to analyze the role of IL-10
on tumor development. The data from in vitro, ex vivo and animal experiments are
complex, pointing to opposite directions regarding the influence of IL-10 on the cancer:
depending on the experimental model, IL-10 seems to favor or inhibit the existence
and progression of tumors.
8.5.1
Tumor-Promoting Effectsof IL-10
IL-10 is able to directly stimulate the growth of certain tumor cells. Klein et al. have
shown that IL-10 is an IL-6-unrelated growth factor for myeloma cells. By inducing
the expression of co-receptors for oncostatin M on myeloma cells IL-10 provoked an
autocrine growth loop [116, 117]. IL-10 is also an autocrine growth factor for other B
cell lymphomas [86, 88, 90]. The role of IL-10 in B chronic lymphocytic leukemia (B-
CLL) is discussed. Some investigators reported that IL-10 enhanced the survival of B-
CLL cells by inhibiting the process of apoptotic cell death, whereas others described
that IL-10 decreased Bcl-2 protein levels and induced apoptosis [85, 118]. Moreover,
IL-10 also acts as an autocrine growth factor for melanoma cells by enhancing proliferation
and prolonged the survival of these cells [119].
IL-10 can convert tumor cells to a cytotoxic T cell lysis (CTL)-resistant phenotype. In
1994, Kiessling et al. reported an about 50% reduction of MHC class I expression in human
melanoma cells after IL-10 treatment. This pretreatment resulted in a dose-dependent
and up to 100% inhibition of autologous CTL-mediated, tumor-specific lysis [120].
Three years later the same group demonstrated that this was mediated by reduced expression
of the so-called transporter associated with antigen processing (TAP)-1 and -2
which results in reduced translocation of peptides to the endoplasmic reticulum, and
therefore in diminished MHC class I peptide loading and cell surface levels [121]. However,
the down-regulation of MHC class I expression results in higher sensitivity of these
cells towards NK cell activity that also can fight tumors ([122] and see below).
IL-10 can inhibit the antitumor immune reactions. One would expect a negative impact
on the function of monocytes, macrophages, CD4 + T cells and on the generation