Target Discovery and Validation Reviews and Protocols

Overview of Immune System 309
sera from patients with breast cancers, we have identified several potential
tumor antigens, such as ADAM10, dihydrolipoamide S-acetyl transferase, and
β-F1-ATPase.
12. Tumor Escape and Self-Tolerance
Cancer poses a difficult problem for immunotherapy because it arises
from the host’s own tissues. T-cells reactive with dominant determinants of
tumor-associated antigens and perhaps subdominant epitopes are deleted in the
thymus during negative selection. Thus, most of the tumor determinants are
expected to be immunologically silent; hence, effective tumor immunity cannot
be induced by tumor cells (87). Moreover, as tumors accumulate neoantigens
during transformation, they also gradually induce tolerance in T-cells against
these neoantigens (52). Thus, one of the major problems faced by tumor immunologists
is the need to find strategies that induce immunity against self-antigens
expressed by tumor cells. The goal of these strategies is to overcome one or
more mechanisms of immune tolerance. During the last years, a number of
approaches have been used by different groups, including the use of antigen
expressed in xenogeneic cells, heteroclitic peptide strategies, xenogeneic DNA
immunization, recombinant viruses expressing tumor antigens, whole cell
vaccines (typically transfected with cytokines or costimulatory molecules), and
exogenous use of cytokines (88).
The absence of efficient tumor-specific immunity can be related to several
mechanisms, such as inadequate APC function and T-cell tolerance toward
tumor antigens, which are seen as self-antigens (89). As mentioned above (see
Fig. 10), initiation of the T-cell response requires stimulation of the TCR via
its peptide/MHC ligand on the APCs as well as co-stimulatory signals (5).
Several signaling events can prevent the initiation of T-cell activation against
tumors, including the CTLA4 pathway (43). Moreover, recent reports indicate
that several subsets of Treg cells are involved in controlling T-cell tolerance
in the periphery. In addition to the naturally occurring CD4+CD25+ cell population,
which has been shown to be continuously produced within the thymus,
other T-cell subsets bearing suppressive ability have been described. Among
these subsets, the most important are IL-10–producing type 1 regulatory (Tr1)
cells and TGFβ-producing Th3 cells (89). These cells can be derived from the
peripheral naive CD4+ T-cell population under particular conditions of antigenic
stimulation (see Fig. 7). In addition to IL-10, CTLA4 plays an essential
role in Treg function. It is constitutively expressed by Treg cells (CD4+CD25+)
but not by other CD4+ T-cell subsets. Tumor cells also secrete immunosuppressive
cytokines, such as TGFβ and IL-10, which can inhibit T-lymphocyte effector
function. Downregulation of these suppressive cytokines by small-interfering
RNAs (siRNAs) may increase tumor immunity (90).