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

134 7 Immunosuppresive Factors in Cancer
between total polyamine levels and monocyte phagocytosis has been reported in patients
with colorectal cancer [299]. Accordingly, treatment of tumor-bearing animals
with polyamine deprivation combined with low-dose cyclophosphamide resulted in
a synergistic inhibition of tumor growth and metastasis associated with enhanced
macrophage tumoricidal activities [300].
7.5.2.2 Effects of polyamines on T lymphocytes
Polyamine synthesis is required for the induction of CTLs and IL-2 responsiveness
[301±303]. CTL differentiation is more affected by the inhibition of polyamine biosynthesis
than CTL proliferation [304]. These data suggest that polyamines are immunostimulating
for T cells. In addition, polyamine deprivation in animals grafted with
Lewis lung carcinoma tumors reverses tumor-induced immunosuppression (decreased
splenic IL-2 production, and depressed levels of CD4 + and CD8 + T cell populations),
but is not associated with any changes in host CTL activity [305].
7.5.2.3 Effects of polyamines on NK cells
Inhibition of polyamine biosynthesis and polyamine deprivation in vivo is associated
with decreased tumor growth and metastases and significantly enhanced NK cytotoxic
activity [267, 306]. Thus, polyamines are inhibitory for NK cells.
7.5.3
Inhibition of Polyamine Biosynthesis: Implications for Therapy
As described above, inhibitors of ODC, polyamine analogs and polyamine-deficient
diets have been used in animal models to suppress polyamine levels. Both ODC inhibitors
and polyamine analogs have been useful in identifying the role of polyamines
on tumor growth and host immunosuppression. However, polyamine inhibition
as a target for cancer treatment is very complicated due to the ubiquitous expression
of polyamines and the contribution of food sources to an individual's polyamine
status, as well as the critical role of polyamines on the proliferation and survival of
both normal and cancer cells. Future studies are required to identify mechanism(s)
to target polyamine inhibitors to neoplastic cells thereby improving the therapeutic
index of these inhibitors.
7.6
Tumor-Shed Immunosuppressive Molecules
In addition to tumor-secreted immunosuppressive cytokines and other intracellularderived
factors, tumors shed many antigens believed to exert immunosuppressive effects.
The most well-characterized immunosuppressive antigens shed from tumors
are the mucins. Mucins are high molecular weight glycoproteins present on most secretory
epithelial tissues. However, most human epithelial tumors over-express aberrantly
glycosylated mucins referred to as MUC-1 and -2 (reviewed in [307, 308]).
MUC-1 has been employed as an immunotherapeutic target for cancer patients be-