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

7.1 Transforming Growth Factor (TGF)-b
scription factors in activated lymphocytes [50]. By contrast, Sudarshan et al. reported
that TGF-b does not block cytokine (IL-12 and IL-2) induced Janus tyrosine kinase
(JAK) and signal transducers and activators of transcription (STAT) phosphorylation
in T cells [51]. Thus, the mechanism by which TGF-b inhibits IL-1- induced T cell
proliferation is not clear and may depend on many factors.
Numerous conflicting reports of the effects of TGF-b on Tcell apoptosis have been described.
TGF-b has been found to induce T cell apoptosis [50, 52, 53] and to prevent
T cell apoptosis [54±59]. These conflicting reports suggest that multiple factors (microenvironment,
origin, as well as differentiation and activation states) influence the
T cell apoptotic response to TGF-b. TGF-b has been reported to promote apoptosis in
T cells independent of the IL-2/IL-2 receptor pathway [52] and through the activation
of caspase-like proteases in activated murine T cells [59]. By contrast, TGF-b when
present during the course of T cell activation inhibits activation-induced cell death
(AICD)and Fas-mediated apoptosis [54]. AICD by T cells is one mechanism for controlling
the size and the duration of the primary immune response. Further studies
show that TGF-b prevents apoptosis in memory T h1 CD4 + T cells [42]. Genestier et al.
have shown that the addition of TGF-b to human T cells and T cell hybridomas significantly
reduced apoptosis after activation by anti-CD3 [58]. TGF-b blockade of
T cell apoptosis was associated with decreased Fas ligand expression and not Fas signaling.
These findings suggest that TGF-b, when present at the right time, functions
as a ªviability factorº allowing the clonal expansion of effector T cells and the generation
of long-lived memory T cells during the immune response. More recently, Sillett
et al. demonstrated the importance of the timing of TGF-b administration for inducing
T cell apoptosis in vitro [60]. TGF-b, when added at the initiation of T cell mitogenesis
did not induce T cell apoptosis, whereas TGF-b added post-activation enhanced
apoptosis in T cells independent of Bcl family members.
7.1.2.3 Effects of TGF-b on NK and lymphokine-activated killer (LAK) activity
NK cells are a subset of bone marrow-derived immune cells that proliferate in response
to viral and cellular invasion. Once activated, NK cells directly kill tumor
cells, but do not require matching of MHC molecules between effector and target
cells. Overall, TGF-b has an inhibitory effect on peripheral blood NK cells [7]. TGF-b inhibits
NK proliferation, cytokine production [IFN-g, TNF-a and granulocyte macrophage colony
stimulating factor (GM-CSF)], NK activation and NK cytotoxicity. [7, 61].
NK cells represent the main precursors of LAK activity. TGF-b inhibits the induction
of LAK cell activity in vitro [62±64] and suppresses the production and the antitumor cytotoxic
activity of LAKs [38, 39].
7.1.2.4 Effects of TGF-b on dendritic cells (DCs)
DCs are critical immune cells responsible for innate and adaptive immunity during
tumor killing (reviewed in [65, 66]). DCs initiate and regulate both cell-mediated and
humoral responses. Immature DCs express abundant intracellular levels of MHC
class I and II molecules which bind specific tumor antigens. Once matured, DCs display
the MHC bound antigen on their surface together with multiple co-stimulatory
molecules (CD40, CD50, CD54, CD58, CD80, CD83 and CD86) and potently activate
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