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

6.5.2
T Lymphocyte Apoptosis in Patients with Cancer
Lymphocytes in the circulation of patients with cancer have been observed to express
Fas and bind Annexin V. As many as 95% of circulating T cells express Fas in some
patients and Fas + CD3 + cells have been shown to preferentially bind Annexin V [99,
100]. These T cells also have high levels of caspase-3 activity and reduced or absent
expression of the TCR-associated z protein [98±100]. The significantly elevated proportions
of T cells with this pre-apoptotic profile in the circulation of patients with
cancer relative to healthy controls suggest that a rapid turnover of T cells occurs in
these patients. As the patients with cancer are generally not lymphopenic, it has to
be assumed that new lymphocytes are being recruited from the precursors in the
bone marrow to replace those undergoing apoptosis. We recently found that
CD3 + CD8 + T cells as well as CD3 + CD8 + CD28 ± and CD3 + CD8 + CD45RO ± CD27 ± subpopulations
of ªeffectorº T cells contained especially high proportions of z low or Annexin-binding
cells in patients with cancer, an indication that these subsets were preferentially
targeted for apoptosis ([100] and unpublished data). Preliminary results
suggest that consumption of sFasL and its binding to Fas expressed by these T cells
may be, in part, responsible for the high proportions of dying T cells seen in the circulation,
because sFasL levels in the patients` sera were found to be significantly decreased
relative to those in the sera of normal age- and sex-matched controls (unpublished
data). Also, there appears to be a significant association between the frequency
of circulating T cells with the pre-apoptotic phenotype and disease activity,
with the highest proportions of Annexin-binding, Fas + T cells and lowest sFasL
serum levels seen in the patients with active disease. In aggregate, these results suggest
to us that in tumor-bearing hosts, effects of the tumor microenvironment extend
far beyond the tumor, and that the presence of tumor has profound effects on
lymphocyte homeostasis, kinetics of recirculation and levels of activation.
6.5.3
Tumor Sensitivity to FasL-Mediated Signals
6.5Mechanisms Linked to Dysfunction of Immune Cells in Cancer
Expression of FasL as well as Fas on the surface of tumor cells implies that tumors
might be sensitive to Fas±FasL-mediated apoptosis. Most human tumors express
more Fas than FasL on the cell surface, as determined by in situ immunostaining
[101]. However, using tumor cell lines, we failed to observe any correlation between
the level of Fas expression and tumor cell sensitivity to FasL-mediated apoptosis
[101]. It appears that Fas, although expressed on tumor cells, is not a functional receptor
in many cases. The mechanisms responsible for resistance of human tumors
to FasL-mediated apoptosis may vary, but in most cases they involve overexpression
of one or another of apoptosis-inhibitory proteins [102]. One of the more extensively
studied inhibitors of the Fas±FasL pathway, cFLIP, interacts with FADD in the DISC
complex, preventing cleavage of pro-caspase 8 and blocking the apoptotic cascade
[102]. Another inhibitor, which may be overexpressed in some tumor cells, is a Fasassociated
phosphatase named FAP-1 [103]. In addition to utilizing these natural in-
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