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

112 6 Immune Cells in the Tumor Microenvironment
hibitors, tumors may down-regulate Fas and thus avoid FasL-mediated death. On balance,
Fas + -activated T cells appear to be much more sensitive to FasL-mediated apoptosis
than tumor cells, which have devised multiple ways of protecting themselves
and surviving.
6.5.4
A Dual Biologic Role of FasL
FasL is a death-inducing as well as pro-inflammatory molecule [104]. In vivo experiments,
in which tumor cells transfected with FasL cDNA and expressing FasL were
implanted in animals demonstrated that, contrary to expectations, such cells were rapidly
rejected and that the rejection was mediated by granulocytes accumulating at
the site of tumor implantation [105]. In an elegant series of experiments, Nabel and
colleagues showed that in mice injected subcutaneously with genetically modified
CT26-CD95L tumor cells, infiltrating neutrophils eliminated the tumor. However,
the same CT26-CD95L cells survived in the intraocular site, because of the presence
in this location of TGF-b, which inhibited p38 MAP kinase activity in neutrophils
and thus disabled their anti-tumor functions. Neutrophils, which accumulated at the
site in response to FasL, were thus unable to exercise their anti-tumor effects in the
presence of TGF-b, with the net result of promoting tumor growth by disabling the
effector cells [106]. Thus, TGF-b was able to override the pro-inflammatory effects of
FasL, an indication that cytokines produced in the tumor microenvironment can regulate
immunosuppressive versus pro-inflammatory activity of this ligand. This ªcontextualº
regulation of FasL activity strongly suggests that the final outcome of interactions
between tumor and immune cells depends on the tumor microenvironment.
It is, therefore, not in the least surprising that conflicting results emerge from various
studies probing these interactions. Furthermore, the diversity of pathways that
might be employed by the tumor in the process of evasion from the host immune
system (see Tab. 6.2) emphasizes the likelihood of individual differences between tumors
of the same type in their interactions with immune cells. In such a case, cellular
and molecular events mediated by the same receptor±ligand pair might be quite
distinct or even opposite in the particular microenvironment. The consequences of
this diversity, as manifested by a successful escape of the tumor from immune control,
will not be easy to deal with from the clinical point of view.
6.5.5
Contributions of other Pathways to Lymphocyte Demise in Cancer
In this review, I have focused on the Fas±FasL pathway to illustrate one of the many
possible mechanisms implicated in mediating death of immune cells in the tumor
microenvironment. It is, of course, highly likely that the other TNF family members
play an equally important role in tumor-effector cell interactions. The TRAIL±TRAIL
receptor pathway in melanoma, for example, has been studied by several investigators,
largely, however, in respect to tumor cell resistance or sensitivity to apoptosis
[107, 108]. There is evidence indicating that TRAIL and other TNF family death-in-