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

7.2 IL-10
lated CD4 + T cells [134, 135]. By contrast, IL-10 does not inhibit IFN-g secretion by
CD8 + T cells in response to tumor stimulation in vivo [136].
However, most often the inhibitory effects of IL-10 on Tcells are mediated indirectly
through its effect on antigen-presenting cell functions. IL-10 suppresses antigen-induced
CD4 + T cell proliferation [129, 134, 135]. Similarly, Steinbrink et al. report that
IL-10 treatment of DCs cells induces alloantigen-specific anergy in both CD4 + and CD8 +
T cells [137, 138]. IL-10 induces T cell anergy (unresponsiveness) when present during
antigen-specific activation [139]. IL-10-induced CD4 + T cell anergy can be reversed by
IL-2 administration or receptor cross-linking (anti-CD3/anti-CD28) [139], as well as
by immunization with mature DCs [140].
The effects of IL-10 on the host antitumor CD8 + CTL responses are somewhat contradictory.
IL-10 has been reported to exhibit both immunosuppressive and immunostimulatory
effects on CD8 + T cells in vitro and in vivo. IL-10 inhibits proliferative
and cytotoxic T cell responses generated in primary MLRs in vitro [141]. In vivo, IL-
10 has been shown to repress CTL activity directly [142] (by inhibiting granzyme B expression
[143]) and indirectly (by inhibiting the generation of functional CTLs [144]).
IL-2 or IFN-grestores the IL-10-suppressed CTL alloreactivity if administered at the
time of tumor challenge, suggesting that the immunosuppressive effect of IL-10 can
be blocked by Th1-type cytokines. In accordance with the immunosuppressive effects
of IL-10 on host CTLs, Sharma et al. examined the growth of Lewis lung tumors in
mice engineered to over-express T cell-derived IL-10 [145]. Over-expression of IL-10 significantly
enhanced tumor growth associated with decreased cytokine production by T cells
(IL-2 and IFN-g), and suppressed cytolytic activity of CD8 + T cells. Furthermore, these
mice produced dysfunctional splenic antigen-presenting cells that expressed significantly
reduced cell surface levels of MHC class I, CD80, CD86 and CD11c molecules.
These dysfunctional antigen-presenting cells could not support MLRs or promote
antitumor CTL induction. Furthermore, DCs obtained from the IL-10 transgenic
mice fail to induce antitumor CD8 + T cell reactivity in vivo following exposure
to tumor-specific peptides. This finding supports previous work showing that IL-10
treatment of DCs reduced their allostimulatory activity for CD8 + T cells and induced
alloantigen-specific anergy in CD8 + T cells [137].
By contrast, IL-10 has been shown to stimulate the host immune system and contribute
to limited tumor growth and metastases [146, 147]. IL-10 enhances cellular recruitment
[148], promotes CD8 + T cell proliferation [139, 149], augments the outgrowth of
CTL precursor cells [150, 151] and enhances cytolytic activity [152]. In vivo, anti-IL-10 reduced
the host primary CTL response in mice following immunization with B7-1 +
P815 tumor cells, suggesting the important role of IL-10 in the host antitumor CTL response
[153]. In accordance with the reported immunostimulating properties of IL-
10, Groux et al. report the enhanced CTL response in IL-10 transgenic mice [154].
Mice engineered to over-express IL-10 in antigen-presenting cells under the control
of the MHC class II Ea promoter exhibited a biphasic pattern of tumor growth in
which the tumors grew rapidly during the first 2 weeks and then completely regressed.
Thus, the effects of IL-10 on the host CTL response is complex; T cell-derived IL-
10 may function as an immunosuppressive factor, whereas antigen-presenting cellderived
IL-10 might act as an immunostimulating factor.
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