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

mulatory molecules) any T cells with reactive TCR are induced to die. During infection,
antigens released from the infected tissue will be released in the immunostimulatory
environment created by the infection (Fig. 10.5A). Now, DCs which pick
up the pathogenic antigens will be able to prime T cell responses against them
whilst tolerance has previously been established for all other cellular antigens
which are co-released. This does not bode well for the development of cancer vaccines
because the antigens involved are predominantly self and will have been
sampled previously ± indeed this may be one mechanism by which immune unresponsiveness
(tolerance) to tumor antigens develop since the tumor site is usually
a site of immunosuppression and the DCs picking up antigens from there will not
be activated. However, once again, the fact that autoimmune disease can develop
despite such processes gives hope that inducing reactivity to self or near-self tumor
antigens will, at least in some circumstances, be viable [35].
The greatest challenge, then, lies in developing antitumor vaccination strategies that
combine efficacy (breaking tolerance to TAAs) with safety (preventing widespread
autoimmunity). These considerations argue strongly that the safest form of antitumor
vaccination would come from protocols using one, or a few, defined, tumor-specific
antigens for which the potential for presentation of specific epitopes of that antigen
is known in the context of the specific MHC haplotype of each patient. In general,
the present view on the most efficacious approach is the converse ± the relative
paucity of known tumor antigens means that vaccines based on whole-cell preparations
should provide a broader portfolio of antigens relevant to the tumor [88]. However,
the whole-cell vaccine approach also increases the risk of liberating non-TAAs
to which potentially self reactivity will be detrimental. If we have a clearer understanding
of exactly which cellular antigens can form the basis of autoimmune reactions
then we may be able to design the cell vaccine approach more precisely to exclude
the possibility of generating deleterious autoimmune reactivity whilst inducing
beneficial antitumor reactivity. This is also a concern when the tumor antigens
are themselves not exclusively restricted to the tumor, but are also expressed on
other, normal cells. In some situations, such as the development of vitiligo whilst undergoing
immune therapies for malignant melanoma [50, 83], the trade-off between
autoimmune destruction of normal tissue and continued development of malignant
disease might be an acceptable bargain. However, in others, such as the prospect of
autoimmune destruction of the colon or brain during immune-mediated treatment
for colorectal cancer or glioma, this might not be the case [32, 34].
10.8
The Way Forward
10.8 The Way Forward
So, in many cancer patients the immune system is probably functioning as well as it
can within the confines of its responsibilities to protect against infectious disease
while avoiding autoimmune disease. We now need to learn how to manipulate antitumor
immunity within these confines and push it in the direction of, but not too
far towards, the generation of autoimmune-like reactivity.
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