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

7
Immunosuppresive Factors in Cancer
Richard Bucala and Christine N. Metz
7.1 Introduction
Tumors have paradoxical effects on the host immune system: they stimulate immune
cells and they suppress immune cells. When host immunostimulation is effective,
tumor cells are destroyed. However, tumors produce several suppressive cytokines
and other factors that subvert the host antitumor immune response. These immunosuppressive
factors function by repressing the host antitumor immune cells
and/or by promoting host immunosuppressor cell activity. Suppression of the host
antitumor immune response occurs by preventing tumor recognition by immune
cells and/or by inhibiting immune cell-mediated tumor killing. An accurate identification
and understanding of the immunosuppressive factors that contribute to the
host antitumor immune response is critical for the effective treatment of cancer patients,
whether by conventional treatments or by newly developed immunotherapeutic
strategies. In this chapter, we will discuss the effects of tumor-derived suppressive
cytokines, factors, and shed antigens on host immune cells (summarized in Tab. 7.1)
and on tumor cells. In addition, we will address the implications for the inhibition of
these immunosuppressive agents during cancer treatment.
7.1
Transforming Growth Factor (TGF)-b
Cancer Immune Therapie: Current and Future Strategies
Edited by G. Stuhler and P. Walden
Copyright # 2002 Wiley-VCH Verlag GmbH & Co. KGaA
ISBNs: 3-527-30441-X (Hardback); 3-527-60079-5
(Electronic)
TGF-b was originally described for its ability to induce NRK rat kidney fibroblasts to
form large colonies in soft agar in the presence of epidermal growth factor [1, 2].
Since its discovery, TGF-b has been shown to play a role in cell growth, differentiation
and transformation, and to modulate the host immune response to tumor
growth and metastases. The TGF-b superfamily consists of TGF-b1, -b2 and -b3, as
well as an additional 40 different TGF-b-related proteins (reviewed in [3]). The three
mammalian isoforms (TGF-b1, -2 and -3) are synthesized as pre-pro-TGF-b polypeptides
that contain a signal sequence, the pro-region [latency associated peptide
(LAP)] and mature TGF-b (N-terminal region). The majority of TGF-b is secreted as
an inactive complex associated with a second gene product known as the ªlatent
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