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

7.4
Prostaglandin (PG) E2
PGE2 is a powerful lipid mediator that influences inflammation, promotes tumor
growth and suppresses the host antitumor immune response. PGE2 belongs to a family
of eicosanoids that are derived from n-3 and n-6 polyunsaturated fatty acids. Its
synthesis is regulated by a series of steps following the cyclooxygenation of arachidonic
acid by two key regulatory enzymes, cyclooxygenase (COX)-1 and -2 (reviewed in
[208]). COX-1 is constitutively expressed, whereas the inducible COX-2 (ªoncogeneresponsive
COXª) is over-expressed by many tumors [209±211].
7.4.1
Sources of PGE 2
PGE2 is expressed by numerous tissues and cell types, including breast fibroblasts
[212], colonic muscle cells and mucosa [213], peritoneal mesothelial cells [214], vascular
endothelial cells [215] and macrophages [216, 217], as well as many tumors and
tumor cell lines including, prostate [218], squamous cell carcinoma of the head and
neck [219], and mammary epithelial cells [220]. PGE2 expression by macrophages
can be induced by tumor cell factors [221] and in tumor-bearing mice [222]. PGE2 expression
often correlates with prognosis in cancer patients [223].
PGE2 promotes tumor cell proliferation [224], enhances tumor cell invasiveness
[218] and down-regulates MHC class II expression by tumor cells [225]. In addition
to its effects of tumor cell growth, invasiveness and metastatic potential, PGE2 has
been shown to promote host immunosuppression during tumor progression.
7.4.2
Effects of PGE 2
7.4.2.1 Effects of PGE 2 on monocytes/macrophages
Host antitumor macrophage activity inversely correlates with PGE2 expression [226].
Although host macrophages are considered to be the major source of PGE 2 during
tumor growth, they express PGE2 receptors [227] and thus, can be rendered dysfunctional
by PGE2. Similar to IL-10, PGE2 inhibits Th1 cytokine synthesis (TNF-a)by
macrophages while promoting ineffective Th2 cytokine production (IL-10) [228]. This ineffective
shift in the host antitumor activity toward a Th2 response by PGE2 during tumor
growth encourages host immunosuppression.
7.4.2.2 Effects of PGE2 on T lymphocytes
7.4Prostaglandin (PG) E2
PGE2 is immunosuppressive to various types of T cells through its inhibitory effects on proliferation,
cytokine production, migration and effector activity (reviewed in [229, 230]).
Very early studies showed that immunization with PGE2 significantly reduced tumor-induced
immunosuppression (as measured by spleen cell proliferation assays)
in mice [231, 232], suggesting the role of PGE 2 in suppressing T cell proliferation.
Further studies using experimental tumor models and anti-PGE2 antibodies demon-
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