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

132 7 Immunosuppresive Factors in Cancer
strated the role of PGE2 in suppressing polyclonal T cell activation and CTL generation
following MLRs by splenic T cells [233]. PGE2 treatment of stimulated peripheral
blood lymphocytes and CD4 + T cells decreases IL-2 and IFN-g production and promotes
IL-10 production [234, 235]. However, CD8 + T cell effector functions are reported to
be more sensitive to the suppressive effects of PGE2 than CD4 + T cells [236]. PGE2
inhibits T cell migration [237], promotes T cell anergy [238], and suppresses CD8 +
CTL activity in vitro and in vivo [239±242].
7.4.2.3 Effects of PGE2 on NK cells and LAK activity
Similar to its immunosuppressive effects on CTLs, PGE2 has been reported to inhibit
NK activity [233, 243±246] and LAK cell activity [233]. These findings correlate with reports
that NK activity inversely correlates with monocyte-derived PGE2 levels, and
that removal of monocytes from the PBMCs of patients with breast cancer restored
NK and LAK levels when compared to healthy controls [247].
7.4.3
Inhibition of PGE2: Implications for Therapy
Slowed tumor growth and the inhibition of metastases has been observed by in vivo
blockade of PGE2 activity using PGE2 immunization [248], anti-PGE2 antibodies
[249] and inhibition of PGE2 production using COX inhibitors [244, 250±254]. Inhibition
of COX-2 (and thus PGE2 production) in an experimental tumor model using
the Lewis lung carcinoma cell line results in a significant decrease in IL-10 production
together with a significant increase in IL-12 secretion, thus restoring host antitumor
reactivity [253]. Similar findings have been observed in COX knockout mice
[255, 256].
The precise mechanisms by which COX inhibitors slow tumor growth are not well
understood. A very recent study by Specht et al. revealed that COX inhibitors enhance
the host CTL responses in an experimental tumor model [252]. More interestingly,
human epidemiological studies suggest the antineoplastic activities of COX inhibitors
[257±259]. However, COX inhibitors also have been associated with the inhibition
of angiogenesis (reviewed in [260]) and tumor growth and telomerase elongation
activity in tumor cells [254].
7.5
Polyamines
Polyamines (putrecine, spermine and spermadine) are natural occurring small organic
cations. Polyamines are critical for both cell proliferation and differentiation
(reviewed in [261]). Much of our knowledge of polyamine bioactivity stems from the
use of inhibitors of polyamine biosynthesis (see below).