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

TGF-b binding proteinº. Thus, activation of the TGF-b complex is a key regulatory
step for controlling its activity. The biological effects of TGF-b1, -2 and -3 are
mediated through the same high-affinity serine-threonine kinase type I and II receptors,
followed by downstream signaling intermediates known as Smad proteins (reviewed
in [4]).
7.1.1
Sources of TGF-b
Almost all cells in culture can be stimulated to secrete TGF-b, including activated
(not resting) macrophages [3], T cells [5], B cells [6], natural killer (NK) cells [7], as
well as numerous tumor cell types including pancreatic [8], prostate [9, 10], lung
[11], colon [12], melanoma [13] and breast carcinomas (reviewed in [14]). Elevated levels
of TGF-b in serum negatively correlate with cancer progression and reduced survival
for many cancers (reviewed in [15]), including nasopharyngeal [16], colorectal
[17], cervical [18], prostatic [9] and gastric carcinomas [19].
Although TGF-b has been shown to inhibit MHC class II expression on tumor cells,
most tumor cells resist the tumor suppressor and growth inhibitory effects of TGF-b.
Tumor cells are rendered insensitive to the suppressive effects of TGF-b by: (1) receptor
down-regulation [20±22], (2) inactivating mutations within the TGF-b receptor
[23±25] and/or (3) anomalies in the post-receptor TGF-b signaling pathway including
the Smad proteins [21, 26, 27]. By contrast, TGF-b has profound direct effects on immune
cells expressing TGF-b receptors and indirect effects on downstream cellular
mediators.
7.1.2
Effects of TGF-b
7.1 Transforming Growth Factor (TGF)-b
7.1.2.1 Effects of TGF-b on monocytes/macrophages
Macrophages are important cellular mediators of the host immune response to tumors.
Macrophages produce cytotoxic molecules, such as tumor necrosis factor
(TNF)-a and nitric oxide (NO) that kill tumor cells and serve as antigen-presenting
cells. Thus, macrophages function as cellular mediators of both Tand NK cell antitumor
activities. The suppressive effects of TGF-b on monocytes/macrophages are
complex, and depend on their origin, differentiation state and cytokine milieu. TGFb
has been shown to block colony stimulating factor-1-dependent proliferation of
bone marrow precursor cells [28] and hence, macrophage production, as well as inhibit
lipoprotein (a)-induced macrophage proliferation [29]. Tumor-derived TGF-b is well
known for its ability to `deactivate' tissue macrophages that express high levels of
TGF-bR1 and TGF-bR2 (reviewed in [30]). TGF-b suppresses the antitumor cytolytic activity
of bone marrow-derived macrophages already activated with interferon (IFN)-g
and lipopolysaccharide [31]. TGF-b inhibits cytokine (TNF-a)and NO production by
macrophages [32±34], an effect reversed by antisense oligonucleotides to TGF-b [35].
Finally, macrophages rendered dysfunctional by TGF-2;b have powerful inhibitory effects
on the development of the host T cell-mediated antitumor immune response.
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