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

these epitopes. However, any T cells which can bind an epitope through presentation
by an activated APC will now recognize any cell that displays these epitopes on their
surface class I molecules. This then illustrates the critical link between the uptake of
antigen by APC in a fully co-stimulatory environment, and the subsequent effector
phase of target cell recognition and killing by fully activated T cells.
In the case of tumor antigens, therefore, the antigen displayed by the tumor cell in
the context of MHC class I needs to be recognized by peripheral T cells bearing
TCRs with the acuity to bind the epitopes derived from the mutated regions of these
proteins, whilst distinguishing these from epitopes derived from wild-type versions
of the proteins (Fig. 10.3). One type of tumor antigen that stands a high chance of
doing this is one that contains novel epitopes created by fusion of self proteins, such
as the Bcr±Abl junction fragment [5]. However, as we discussed above, many oncogenic
mutations are very subtle (e.g. point mutations in oncoproteins such as Ras).
There are likely to be only a few T cells with TCRs which have the fine structure to
distinguish a self from a near-self epitope (Fig. 10.3B), unless the changes in the nearself
epitope are very significant. Any such T cells would be critically valuable in clearing
tumor cells, but not related, normal cells (Fig. 10.3C). In addition, a small number
of peripheral T cells might retain the ability to recognize unaltered self epitopes,
There are three reasons why this might occur: (1) a self antigen might resemble a
foreign antigen ± a phenomenon known as molecular mimicry (see Appendix), (2) T
cells carrying low-affinity TCR for an antigen might have been overlooked by the process
of thymic deletion as described in Box 10.1 and Fig. 10.3 or (3) there might be a
lack of central tolerance to the antigen because it is inaccessible to thymic APCs during
the formation of the T cell repertoire [6]. Therefore, the T cell armory available
for the war on cancer is probably populated by T cells carrying, at best, TCRs that can
only weakly recognize subdominant epitopes (see Appendix) of self proteins and/or
weakly immunogenic epitopes of TAAs derived from mutated self proteins (Fig.
10.3). The existence of such T cells is tolerated (Box 10.1) because even if they become
inadvertently activated to recognize self antigens, that recognition might not
lead to catastrophic autoimmune disease. An example of this is vitiligo, the skin depigmentation
that occurs in some patients undergoing treatment with melanoma
vaccines, when an effective immune response is generated not only against the melanoma
cells, but also against melanocytes [7].
It is this army of ªsecond-rateº Tcells that we must collaborate with in devising antitumor
immunization strategies (Fig. 10.3). The next question, then, is how we manipulate
these intrinsically weak responses to make them resemble responses to
truly foreign antigens.
10.5
Playing to Strengths
10.5 Playing to Strengths
In the immune responses against pathogenic infection, the immune system is working
against a set of clearly defined, outstandingly foreign antigens. These antigens
are usually associated with overtly inflammatory, pathological situations ± such as
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