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

TGF-b occurs by both proteolysis including subtilisin-like proprotein convertases, such
as furin [84], plasmin, tissue and urokinase plasminogen activator [85] and transglutaminase
[86, 87], and by non-proteolytic mechanisms, such as thrombospondin [88±91]
and by mannose-6-phosphate/insulin growth factor II receptor interactions [92].
Recent investigations highlight the importance of TGF-b activation by subtilisin-like
convertases, such as furin [84, 93]. Like TGF-b, furin is ubiquitously expressed. Recent
studies show that the formation of active TGF-b by glioma cells in vitro can be
blocked by agents that specifically inhibit the enzymatic activity of furin [94]. Thus,
the development of agents that block the activation of the latent TGF-b complex may represent
a new class of anti-immunosuppressive agents for the treatment of cancer.
Although much is known about the specific suppressive effects of TGF-b on immune
cells in vitro, the precise role of TGF-b in host immunosuppression during tumor
growth in vivo is not well understood. Obviously numerous factors play a role in
the host immune response to TGF-b during tumor growth and TGF-b is not always
associated with immunosuppressive activities, e.g. (1) high expression of TGF-b is
not always associated with a poor prognostic outcome [95, 96], (2) over-expression of
TGF-b in experimental models does not always lead to tumor formation and immunosuppression
[97] and (3) the host response to tumors over-expressing TGF-b can
vary depending on the site of tumor implantation [98]. However, most researchers
and clinicians would agree that further studies investigating the potential use of
TGF-b inhibitors to reduce cancer-induced immunosuppression are justified.
7.2
IL-10
Human IL-10 is a homodimeric 17±20 kDa glycoprotein exhibiting a high degree of
homology with the non-glycosylated mouse IL-10 (reviewed in [99]). Unlike TGF-b,
it is synthesized and released as an active cytokine. It signals through the IL-10 receptor,
a member of the IFN receptor family (reviewed in [99]). The IL-10 receptor,
which is expressed on numerous immune cells, is composed of two subunits: IL-10
receptor 1 (ligand binding subunit) and IL-10 receptor 2 (signaling subunit).
7.2.1
Sources of IL-10
7.2 IL-10
IL-10 was originally identified as a product of Th2 cells in response to antigen stimulation
in the presence of antigen-presenting cells [100]. IL-10 is expressed by other
immune cells including: naive and memory T cells, B cells, and monocytes (reviewed
in [99]), as well as tumor (melanoma)-infiltrating T cells [101, 102], NK cells [103]
and peritoneal monocytes present in the malignant ascites of ovarian cancer patients
[104]. Many solid tumors express IL-10 in vitro and in vivo including lung tumor nodules
[105], melanoma [106] and gliomas [107]. In addition, leukemic tumors originating
from the peripheral and bone marrow (including T and B cells) [108], including
Hodgkin's [109] as well as non-Hodgkin's lymphomas [110], express high levels
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