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

ducing ligands and receptors for these ligands are expressed by both human tumor
cells and lymphoid effector cells [109, 110]. The ability of activated lymphocytes to
cross-link the death receptors on tumor cells, thus bringing about death of the target,
has been demonstrated in ex vivo experiments [110]. The most efficient apoptosis of
target cells occurs when at least three different TNF family ligands act in concert, allowing
for delivery of a strong apoptotic signal [110]. At the same time, tumor cells,
which also express a broad panopoly of membrane-associated TNF family ligands,
have the potential of inducing apoptosis in immune cells by a comparable mechanism
acting in a reverse direction. The end-point of this interaction is death of one or
the other party, depending on the microenvironmental factors which regulate not
only the number of immune cells at the site but also levels of expression of the relevant
receptors and ligands.
Not all effector±tumor cell interactions are mediated by the TNF family of receptors
and ligands. Thus, there is considerable interest in and convincing evidence for the
mechanism involving activation of macrophages or granulocytes in cancer patients
either in situ or in the circulation, respectively, and oxidative stress mediated by hydrogen
peroxide they produce [111, 112]. Release by an oxidative burst of ROM from
these cells is thought to lead to z degradation in T and NK cells and to the inhibition
of their functions, including NF-kB activation, and alteration in the cytokine production
profile by these immune cells [112, 113].
Finally, the highly controversial but slowly and grudgingly acknowledged mechanism
of the production of immunoinhibitory factors by the tumor has to be factored
in (see Tab. 6.1). The controversy largely has to do with biochemical purification and
cloning of the purported inhibitory factors. The situation resembles that in the cytokine
field a dozen or so years ago, when soluble, unpurified and uncharacterized soluble
factors were being introduced as regulators of multiple cellular interactions. Today,
several of these cytokines and a handful of cloned soluble factors are known to
be produced by the tumor, and to regulate not only tumor growth but also its relationship
with immune cells (reviewed in [13]). The increasingly important role in
these cellular interactions of metalloproteinases and their inhibitors, TIMP(s), cannot
be overemphasized [114]. However, the major question of who controls these mechanisms
(the tumor or the immune system) has not yet been answered. Hence,
there is enormous interest in the mechanisms exercised by these interacting systems
in patients with cancer and much controversy still surrounds the accumulating evidence
that the tumor may be masterminding the outcome in its favor.
6.6
Conclusions
6.6 Conclusions
T lymphocytes present at the tumor site or in the circulation of patients with cancer
have depressed functions and are more sensitive to apoptosis than their counterparts
in non-cancer lesions or in the circulation of healthy donors. Evidence is emerging
that subsets of CD3 + CD8 + anti-tumor effector cells may be selectively or preferentially
destined to die in cancer patients. However, a controversy has developed in re-
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