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

ackup help from the many checkpoints that must be overcome purely at the level of
cell growth and differentiation control to generate a malignant cell [3]. Simultaneously,
autoimmune disease is also largely avoided by not having a trigger-happy
immune system perpetually able to recognize small variants of self antigens. So, if
the sensitivity of the immune system is set at a level that is optimal for propagation
of the species, might we be able to give it a boost by tipping the balance towards recognition
of tumor antigens? To find out whether this is possible, we need to understand
the nature of tumor antigens and immune responses to them.
10.3
Tumor Antigens and Responses to Them
At best, tumor-associated antigens (TAAs) are overtly foreign, e. g. many cervical cancer
cells express the papillomavirus oncoproteins E6 and E7. However, much more
commonly they are either immunologically `near-self ' or `self '. Self antigens are not
altered in any way with respect to the same protein expressed in normal cells. Other
proteins in a cancer cell are mutated versions of the corresponding normal protein.
These mutations are most often directly responsible for cellular transformation and/
or metastasis. Epitopes derived from the mutated parts of these antigens will have a
different structure from those epitopes derived from the normal cellular counterparts.
The differences are usually at only one or a few amino acid positions and so
these antigens are termed near-self (Fig. 10.2D). As near-self epitopes diverge in
structure (sequence) from the corresponding self epitopes, so the chances of T cells
with T cell receptors (TCRs) reactive to them increases ± the dividing line between
where near-self becomes foreign determines the ability of the immune system to recognize
and destroy tumor cells (Fig. 10.3). In addition, some non-mutated self proteins
can be expressed on tumor cells but not expressed on other adult tissues. Thus,
some melanoma-associated antigens are only expressed normally during early development,
but are switched off at later times (except in a very few restricted tissues).
These antigens, when expression is reactivated within tumor cells, can therefore
serve as target antigens since they are effectively now tumor specific. Finally, tumor
cells can also express self antigens which are expressed at higher levels than they are
normally expressed on other tissue types. Since density of expression can act as a signal
for T cell recognition of antigens, especially for T cells with low-affinity TCR recognition
of antigen, self antigens can also be effectively near-self if they are over-expressed
on the tumor cells (Fig. 10.2) [4, 5].
10.4
Antigen Presentation ± A Resume
10.4 Antigen Presentation ± A Resume
So, at least in theory, tumors are likely to express at least some epitopes that could
form the basis of immune recognition. However, antigen expression alone is not enough.
For antigens to be recognized, and reacted to, by the immune system, they
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