Target Discovery and Validation Reviews and Protocols

310 Sioud
Although much of the initial attention focused on the role of Treg cells in
controlling autoreactivity, there is growing evidence that they significantly
impact on the host response to cancer. In murine models, antibody-mediated
depletion of CD25+ Treg cells enhanced the induction of tumor immunity
(90,91). However, specific depleting antibodies are limited; therefore, new
strategies to modulate survival or apoptosis of Treg are warranted. Reduction of
CD25 Treg cells triggered by certain drugs has been shown to enhance tumor
immunity elicited by vaccination (92).
An additional and highly significant form of immune escape is the ability of
tumor cells to evolve mechanisms that impede antigen processing and presentation,
expression of costimulatory molecules, or a combination (89). Recent
studies demonstrated that some tumor cells could overexpress inhibitors of T-cell
activation, such as galectin. Thus, a tumor may directly inhibit antitumor responses
by multiple mechanisms (52).
The immunoediting model predicts that in all cases, clinically detectable
tumors will develop and may result in death of the host. However, it cannot
explain why tumors are sometimes spontaneously rejected (93). In some
patients, long-term remission was observed without treatment. Thus, surviving
tumors that acquired insensitivity to immunologic detection, elimination, or
both are destroyed! In my opinion, the analysis of the immune responses in this
category of patients who spontaneously recovered from cancer should facilitate
the design of better vaccines. More recently, we have found that some patients
with breast cancer have developed an antitumor immune response with diversification
of B- and perhaps T-cell epitopes (94). This process, generally termed
“epitope spreading,” was found in all destructive autoimmune diseases (94).
Epitope spreading is more likely to depend on many factors, including the
nature of the autoantigen(s) and the level of established immunologic tolerance.
Thus, the identification of tumor antigens capable of triggering a strong
immune response with epitope spreading should be considered as invaluable
candidates for cancer vaccines.
13. Dendritic T-Cells and Cancer Vaccines
One of the immune cell types that link innate and adaptive immunity and play
a major role for cancer immunotherapy is DCs (95,96). These cells are able to
affect immunity through several signals, leading to either activation or inhibition
of T-cell response (96). DCs, via the production of soluble cytokines, also activate
other cell types such as NKT cells and NK cells. Immature DCs are highly
phagocytic, but in the absence of co-stimulation, their activation can lead to tolerance
(97). Under normal conditions, phagocytosed self-antigens should lead to
the induction of tolerance to self and thereby prevent autoimmunity (Fig. 7).
However, immature DCs that captured exogenous antigens undergo maturation,