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

6.5Mechanisms Linked to Dysfunction of Immune Cells in Cancer
Tab. 6.2 Molecularly defined immunoinhibitory factors produced by human tumors a
1. TNF family ligands induce apoptosis via the TNF family receptors
FasL Fas
TRAIL TRAIL-R
TNF
2. Cytokines
TNF-R1
TGF-b inhibits perforin and granzyme mRNA expression;
inhibits lymphocyte proliferation
IL-10 inhibits cytokine production, including that of IL-12
granulocyte macrophage colony promotes expansion of immunosuppressive tumor-
stimulating factor
associated macrophages [119]
ZIP (z-inhibitory protein)
3. Small molecules
mediates degradation of z or inhibits its mRNA
expression [120]
prostaglandin E2
inhibits leukocyte functions via increased cAMP
epinephrine inhibits leukocyte functions via increased cAMP
ROM
4. Viral-related products
inhibits leukocyte functions via superoxide generation
p15E (CKS-17, synthetic peptide) inhibits production of type I cytokines, up-regulates
IL-10 synthesis
EBI-3 (homologue of IL-12 p40) inhibits IL-12 production
5. Tumor-associated gangliosides inhibit IL-2-dependent lymphocyte proliferation,
induce apoptotic signals, suppress NF-kB activation,
interfere with DC generation
a This partial listing of tumor-associated immunoinhibitory factors has been modified from a review by
Whiteside and Rabinowich [13]. It demonstrates the diversity of mechanisms that human tumors are
known to have evolved in order to incapacitate the host immune system.
cubation of activated T cells with tumor cells induces signaling defects, impaired
functions and apoptosis [13, 35]. Table 6.2 is a partial list of tumor-derived factors
that have been described to exert immunosuppressive effects. Second, TAM or
TADC upon ingesting apoptotic or necrotic tumor cells or activated by TAA±antibody
complexes may be a source of oxidative radicals, immunosuppressive cytokines or
suppressive small molecules, as described above. Third, subsets of TIL could become
activated and exercise suppressive functions with respect to other T cells present in
the microenvironment. It is possible, even likely, that all three scenarios are simultaneously
enacted in tumors. Their interplay may vary, depending on the local conditions.
It is certain, however, that this interplay leads to sustained local and systemic
suppression of anti-tumor immune cells in tumor-bearing hosts. A mechanism that
may be common to all three, and is certainly utilized by tumors and T lymphocytes
involves the apoptosis-inducing members of the TNA family of receptors and ligands.
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