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

128 7 Immunosuppresive Factors in Cancer
7.2.2.3 Effects of IL-10on NK cells
Overall, IL-10 exerts an immunostimulatory effect on NK cells. NK cells exhibit low level
IL-10 receptor expression and treatment of NK cells with IL-10 potentiates NK cytokine
production and enhances NK cytotoxicity toward NK-resistant tumors in vitro [155].
Furthermore, IL-10 alone has no effect on NK proliferation, but IL-10 augments IL-2 induced
NK proliferation [155]. These in vitro findings have been confirmed by in vivo studies.
In experimental tumor models, IL-10 injection or IL-10-secreting tumor cells inhibit
tumor metastases by an NK-dependent mechanism [147, 156, 157]. Thus, unlike
the majority of the host immune system that is stimulated by IL-10 blockade during
cancer therapy, NK cell production and activity is reduced by IL-10 inhibition.
7.2.2.4 Effects of IL-10on DCs
DCs are central cellular inducers of the host antitumor immune response because of
their potent antigen-presenting capacity and T cell co-stimulatory abilities. The majority
of published studies support the immunosuppressive effects of IL-10 on DCs.
IL-10 treatment of DCs reduces their capacity to stimulate CD4 + and CD8 + T cell responses
and promote T cell anergy [137, 138]. Tumor expression of IL-10 has been shown to prevent
the migration and accumulation of DCs within tumors, thus suppressing GM-
CSF-induced antitumor responses [158].
The functional activities of DCs during cancer and cancer immunotherapy depend
on their state of maturation. In vitro, exogenous IL-10 inhibits the generation of mature
monocyte-derived DCs in response to GM-CSF and IL-4 [159], and promotes the differentiation
of immature DCs into macrophage-like cells with decreased MHC class II expression
and suppressed phagocytosic capacity exhibiting no IL-12 expression [159±
161]. A similar reduction of MHC class II and co-stimulatory molecule expression
was observed in IL-10-transduced DCs when compared to control gene-modified
DCs [162]. These IL-10-transduced DCs cannot induce T cell proliferation; however,
they can augment CTL generation and NK cell activity. A very recent study by Corinti
et al. found that autocrine production of IL-10 by DCs prevents their spontaneous
maturation of monocyte-derived DCs and treatment of immature DCs with anti-IL10
antibody enhances the expression of MHC and co-stimulatory molecules (CD80,
CD83 and CD86) and cytokines (TNF-a and IL-12) [163]. Thus, IL-10 appears to exhibit
complex and multifunctional activities on DCs of the immune system.
Finally, IL-10 induces spontaneous DC apoptosis [164]. Thus, the immunosuppressive
effects of IL-10 on DC generation, activity, migration and survival may limit the effectiveness
of DC-based antitumor vaccines that are being used in clinical trials for
the treatment of various forms of cancer. An improved understanding of the regulators
of tumor-derived IL-10 expression and the development of appropriate anti-IL-
10 strategies may improve DC trial outcomes.
7.2.3
Inhibition of IL-10: Implications for Therapy
Although not as well developed as anti-TGF-b strategies, several IL-10 inhibitory
treatments have been considered for the improvement of the host immune response