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

124 7 Immunosuppresive Factors in Cancer
resting or naive CD4 + and CD8 + T cells to promote their differentiation into functional
helper and effector (tumor killing) T cells. Thus, the most important function
of DCs is to sensitize the immune system to specific antigens. Because DCs are 10±
100 times more potent antigen-presenting cells than cells and monocytes/macrophages,
much work has focused on their use to stimulate immunity against cancer
(reviewed in [65]).
TGF-b is immunosuppressive to DCs by its ability to block the GM-CSF-induced maturation
[defined as CD86 and MHC class II expression and mixed lymphocyte reaction
(MLR)-stimulating activity] of DCs from mouse bone marrow progenitor cells [67].
In addition, TGF-b over-expressing murine bone marrow-derived DCs exhibit lower allogeneic
T cell stimulatory activity (assessed by MLR and CTL assays than non-transduced
cells) [68]. Thus, TGF-b suppresses important DC activities required during
host antitumor responses.
DCs must localize, presumably from the bone marrow to the tumor site where specific
antigens are present, and then antigen-loaded DCs must migrate to lymphoid tissue
to function optimally as antigen-presenting cells. However, little is known about
the directed migration of DCs in vivo. Recent studies show that TGF-b reversibly regulates
human DC chemotaxis in vitro [69]. TGF-b enhances the expression of CCR1,
CCR3, CCR5 and CXCR4 on immature DCs, and promotes their chemotaxis in vitro.
However, the transcriptional expression of CCR7 by mature DCs is suppressed by
TGF-b. Therefore, TGF-b might promote the migration immature DCs, but inhibit the localization
of mature DCs to the lymphoid organs during the host immune response to tumors.
7.1.3
Inhibition of TGF-b: Implications for Therapy
Numerous methods for inhibiting the immunosuppressive effects of TGF-b during
tumor growth in experimental models have been described. The biological activity of
mature TGF-b can be controlled by suppressing the production of TGF-b or by inhibiting
the activity of mature TGF-b and/or by altering its interaction with TGF-b receptors
on immune cells. Examples of direct inhibition of TGF-b activity/production
during tumor growth to improve the host immune response include: soluble TGF-b
receptors [70], non-signaling TGF-b binding proteins such as decorin [71±73] and a2macroglobulin
[74], neutralizing anti-TGF-b antibodies [75±77] and antisense oligonucleotides
[78±80]. Interestingly, numerous cytotoxic agents also inhibit TGF-b secretion
by malignant glioma cell lines [81]. In addition, TGF-b immunoneutralization
significantly enhances the sensitivity of human breast carcinoma cells to cisplatin-mediated
cytotoxicity in vitro [77], suggesting that TGF-b blockade during chemotherapy
treatment may promote tumor cell killing.
Although there are a few reports describing the secretion of biologically active TGF-b,
the majority of TGF-b is secreted as a latent complex. This latent TGF-b complex is
then activated to release mature TGF-b consisting of two identical disulfide-linked
polypeptide homodimers (reviewed in [82, 83]). Therefore, activation of the latent TGF-b
complex appears to be the major regulator of TGF-b activity in vivo. Activation of latent