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

114 6 Immune Cells in the Tumor Microenvironment
spect to the mechanism of effector cell death in cancer patients. To a large extent,
this controversy exists because of a current incomplete understanding of molecular
pathways that lead to death of certain but not other subsets of lymphocytes found in
the tumor microenvironment. In addition, the existing animal models of tumor
growth appear to be inadequate for clarification of these phenomena, for a simple
reason that murine tumors appear to be much less immunosuppressive than human
tumors. It is also necessary to recall that a wide variety of signals can induce apoptosis
in immune effector cells, including drugs, cytokines, irradiation, low pH, oxygen
intermediates, stress and others [115]. Caspase activation can be induced in hematopoietic
cells independent of the expression of death receptors [116]. As reviewed
above, a broad variety of tumor-derived factors have been identified as contributors
to functional impairment and death of immune cells in tumor-bearing hosts. In this
context, it seems reasonable to coin the term TICD to more accurately define a general
phenomenon of immune cell demise in the tumor microenvironment. This definition
is broad enough to include AICD of lymphocytes, which upon reaching a certain
stage of activation commit suicide or murder other lymphocytes [117]. It also includes
a possibility of the direct engagement of death receptors on immune cells by
the corresponding ligands expressed on tumor cells. Further, it recognizes the fact
that chronic antigenic stimulation existing in the presence of the tumor probably
plays a major role in shaping responses of immune cells. Operationally, therefore,
tumor-specific T cells in the tumor-bearing host are dying of AICD, which is initiated
or staged by the tumor.
Given the existing evidence for dysfunction and death of Tcells in the tumor-bearing
hosts, it is necessary to identify and evaluate therapeutically promising strategies for
protection of immune cells in the tumor microenvironment. Preliminary studies
suggest that cytokines or DC-based vaccines might be able to offer such protection
from apoptosis to immune effector cells. Although therapy with cytokines, IL-2,
IFNs or IL-12, has been used by numerous investigators to treat malignancies in recent
years (reviewed in [118]), it has never been specifically directed toward preventing
death of immune effector cells. On the contrary, the rationale behind cytokinebased
therapy has been up-regulation of anti-tumor functions of immune effector
cells, especially T cells specific for the tumor. In retrospect, it seems that attempts to
up-regulate functions of cells that are dying in the tumor microenvironment are not
likely to succeed. A new strategy for cytokine delivery and perhaps new cytokines are
necessary to rescue the dying cells or, better, to protect them from death-inducing
signals. It is hoped that in the future, this long-neglected aspect of immunotherapy
will receive the attention of both basic and clinical investigators. There is a certain
degree of urgency associated with the implementation of new strategies for immunotherapy
of cancer in view of extensive vaccination efforts on-going world wide in
patients with malignancies. These clinical trials, largely conducted with patients
who have advanced disease, are not likely to succeed if only a proportion of the vaccine-induced,
tumor-specific effector cells survive in vivo. To avoid likely disappointments,
it will be necessary in the future to combine anti-tumor vaccines with therapies
providing protection of activated T cells from tumor-induced apoptosis.