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

96 6 Immune Cells in the Tumor Microenvironment
of the immune cells in the tumor microenvironment has been generally taken as a
sign that the tumor is not ignored by the host immune system, it is important to point
out that the earliest stages of tumor progression defined morphologically, i.e. hyperplasias
and dysplasias, appear to be invisible to the immune system. There may be at least
two explanations for this lack of the visible involvement of immune cells in the earliest
phase of tumor growth: (i) the genetic modification in the tumor cell does not result in
the phenotypic change at its surface and remains ªsilentº or (ii) the genetic change is
noted, the immune response is made and the genetically unstable tumor under immune
pressure develops immunoresistant variants, the phenomenon referred to as
ªimmune selectionº. The immunoselection alternative appears to fit with the immune
surveillance theory introduced some years ago by F. M. Burnett and others, which defined
the immune system as the primary mechanism for elimination of transformed
cells [2, 3]. In the modern re-interpretation, the immune surveillance hypothesis emphasizes
the ability of the immune system to detect tumor cells and to destroy them.
Thus, it is currently accepted that tumors are not ignored by the host immune system.
On the other hand, it is also clear that tumors are not passive targets for immune intervention.
Modern immune surveillance theory is based on the premise that interactions
between the tumor and immune cells or their soluble products are complex, bi-directional
and often result in the demise of immune rather than tumor cells.
With the identification of multiple tumor-associated antigens (TAA), which induce
either humoral or cellular immune response or both, a scientifically justifiable rationale
for the testing of TAA-specific immunotherapies has been obtained [4±6]. Yet, relatively
modest clinical responses to these therapeutic interventions in recent years
beg the question of why it has been so difficult to induce and maintain tumor-specific
responses in man. In an attempt to answer this question, it becomes necessary to consider
the interplay between the tumor and immune cells that takes place in the tumor
microenvironment during tumor progression. Figure 6.1 is a pictorial attempt to explain
some of these interactions in comparison to events that occur during the infection
by an exogenous pathogen. This comparison contrasts the vigorous cellular and
antibody responses generated to viral or bacterial antigens (Fig. 6.1A) with a relatively
weak immune responses to TAA (Fig. 6.1B). At least one reason for the lack of robust
immune responses to the tumor is the absence of a ªdanger signalº in the tumor microenvironment
[7, 8]. The immune system perceives infections as ªdangerº and the
tumor as ªself º. It responds vigorously to contain the external danger introduced by a
pathogen and only weakly, if at all, to TAA, which are largely self-antigens or altered
self-antigens (Fig. 6.1). Tolerance to self that needs to be overcome for a full-scale immune
response to TAA is one, but not the only, detriment to the generation of effective
anti-tumor immune responses [9]. The nature of the tumor microenvironment characterized
by the presence of immunosuppressive factors, and by the excess of antigens
produced and released by the growing tumor is clearly not the optimal venue for the
immune cells. However, the immune response to the pathogens or TAA takes place in
the lymph nodes draining the infected tissue or the tumor and not in the tumor microenvironment.
It is, therefore, reasonable to postulate that effects of the pathogen and
the tumor alike are not only local but also systemic, affecting the host immune system
as a whole. As discussed below, this appears to be the case.