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

7.2 IL-10
during tumor growth in vivo. These include neutralizing IL-10 antibodies [165, 166],
anti-IL-10 receptor antibodies [104], IL-10 antisense strategies [158, 167], drugs [168]
and the removal of IL-10-producing suppressor T cells [169]. However, not all studies
report improved host antitumor immune responses following IL-10 inhibition or depletion.
In vivo, IL-10 gene-transfected melanoma [146] and mammary adenocarcinoma
cells [170] significantly reduced the tumorigenic and metastatic potential of
these cells in mice and appear to be anti-angiogenic. Similarly, injection of IL-10 resulted
in the inhibition of both B16-F10 melanoma metastases and spontaneous
melanoma development in experimental models [147]. The antitumor activity of IL-
10, in part, is mediated via IFN-g (inducible NO synthase and NO) [171]. Thus, an
improved understanding of the role of IL-10 inhibition on host immunosuppression
during cancer therapies is warranted.
7.2.3.1 Antibodies
Anti-IL-10 antibodies have been shown to up-regulate anticancer autoreactive T cell
responses by inhibiting macrophage suppressor activity in vitro [165]. Anti-IL-10 promotes
survival in tumor-bearing mice, and enhances host CTL activity in vivo, as
well as the production of IL-2, IL-12 and IFN-g by host spleen cells [166]. Recently,
Loercher et al. showed that anti-IL-10 receptor antibodies block the inhibition of phytohemagglutinin-stimulated
T cell proliferation induced by IL-10-secreting peritoneal
monocytes obtained from ovarian cancer patients [104]. This finding suggests that
inhibition of IL-10 signaling in immune cells might promote the production of antitumor
T cells.
7.2.3.2 Drugs
Cyclophosphamide (low dose) has been used during active specific immunotherapy
in patients with advanced melanoma and other metastatic cancers [172, 173]. The
principle of using cyclophosphamide is to selectively reduce suppressor cell activity
and to inhibit the production of suppressive factors such as TGF-b, IL-10 and NO
while promoting antitumor immunity during tumor vaccine strategies [168]. A recent
study by Matar et al. showed that low-dose cyclophosphamide treatment in lymphoma-bearing
rats exhibiting an impaired lymphocyte proliferative response led to
a decrease in IL-10 production by T cells and, consequently, a shift in the immune response
from suppression toward immunopotentiation [174]. This state of immunostimulation
was accompanied by reduced tumor growth and metastases in cyclophosphamide
treated animals.
7.2.3.3 Removal of the source of IL-10
gd T cells accumulate in early tumor lesions and spleens of tumor-bearing animals
and express both TGF-b and IL-10. Therefore, depletion of these suppressor cells
might lead to enhanced antitumor immune responses. Seo et al. recently demonstrated
that lysis of tumor-associated gd cells using a daunomycin-conjugated anti-gd
antibodies improved host tumor-specific NK and CTL responses, and resulted in tumor
regression in an experimental tumor model [169]
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