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

126 7 Immunosuppresive Factors in Cancer
of IL-10. The general effect of IL-10 on tumor cells themselves is protective. Pretreatment
of tumor target cells with IL-10 defends them from allo-specific CTL lysis
[111, 112]. In addition, IL-10 treatment of tumor cells down-regulates their expression
of the NK target molecule structure which mediates NK cell-mediated antitumor
cytotoxicity and, thus, protects them from NK cell-induced lysis [113]. Furthermore,
very recent studies demonstrated that tumor cells use IL-10 as an anti-apoptotic
factor to protect themselves against cytotoxic drugs [114]. However, tumor cells
also secrete IL-10 to manipulate the host antitumor immune response.
Elevated serum IL-10 is considered a negative prognostic indicator for numerous
cancers including Hodgkin's disease [115±117], metastatic melanoma [118] and pancreatic
cancer [8]. Circulating IL-10 often serves as a potential marker for (1) the progression
from adenoma to carcinoma, (2) metastastic disease and (3) the degree of
malignancy [106, 119, 120]. Based on the significant relationship between serum IL-
10 levels and the time to treatment failure and overall survival, IL-10 appears to be
an important indicator for monitoring disease progression in cancer patients (reviewed
in [121]). Although IL-10 exhibits some ªanti-angiogenic activityº [122, 123],
it has been shown to promote tumor growth by significantly suppressing the host
immune response.
7.2.2
Effects of IL-10
7.2.2.1 Effects of IL-10on monocytes/macrophages
IL-10 was first described as ªcytokine synthesis inhibitory factorº. IL-10 inhibits cytokine
synthesis (IL-1, IL-6, IL-8 and IL-12) by monocytes/macrophages induced by lipopolysaccharide
[124, 125]. In addition, IL-10 regulates the production of another potent immunosuppressive
agent, prostaglandin, by macrophages [126] and inhibits NO production
and the cytotoxic activity of monocytes/macrophages [127, 128].
IL-10 reduces the antigen-presenting capacity of certain classes of macrophages by multiple
mechanisms. IL-10 suppresses cell surface MHC class II expression by macrophages
[129], in part by inhibiting the transport of peptide-loaded MHC molecules to the
plasma membrane [130]. IL-10 also inhibits the surface expression of CD80 and CD86,
as well as other important co-stimulatory molecules [131, 132]. In summary, by manipulating
cytokine production by macrophages and the expression of important cell
surface molecules, IL-10 reduces the cytotoxic activity and antigen-presenting capacity
of macrophages to specific T cells and, thus, suppresses the host antitumor immune
response. Furthermore, macrophages obtained from tumor-bearing hosts are
more susceptible to the immunosuppressive activities of IL-10 and less sensitive to
immunostimulatory factors necessary to mount an effect antitumor response [133].
7.2.2.2 Effects of IL-10on T lymphocytes
IL-10 directly affects T cells by interacting with membrane associated IL-10 receptors
and indirectly through the suppressive effects of IL-10 on antigen-presenting cells. Similar
to its effect on monocytes/macrophages, IL-10 directly inhibits cytokine production
by T cells. IL-10 inhibits type I cytokine (IL-2 and TNF-a)production by stimu-