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

222 10 The Immune System in Cancer: If It Isn't Broken, Can We Fix It?
Key advances in the coming years will come from the ability to profile each type of
tumor to determine the range of antigens that are expressed. Eventually it will be
possible to match these expression profiles with those antigens known to be truly
self, and against which no residual T cell reactivity can exist within a specific patient's
MHC haplotype. In contrast, other antigens will match with those for which
some T cells are likely to exist with at least some capacity to recognize self or nearself-derived
epitopes. To get to this stage, deeper understanding of the mechanisms
of central and peripheral tolerance will be required [6]; greater numbers of immunologically
relevant tumor-specific antigens will have to be described [4, 5]; the epitopes
of these antigens will need to be mapped and their relationship to different
MHC haplotypes determined. In this way, it might genuinely be possible to match
tumor expression and patient MHC haplotype profiles to predict which antigenbased
vaccine strategies stand a reasonable chance of success. Simultaneously, it
will be necessary to develop effective ways to associate the expression of these antigens
with immunologically dangerous/pathological situations that resemble the situations
to which the immune system reacts extremely aggressively (Fig. 10.4).
One particularly good way to do this might simply be to place those antigens in appropriately
activated DCs for adoptive transfer to the patient [51, 52]. In addition,
study of autoimmune initiating mechanisms will help immunotherapists understand
the activities and therapeutic value of novel adjuvants, both in the context of
molecular mimicry with tumor antigens and in their ability to initiate epitope
spreading [36]. Advances in the treatment of autoimmune disease will also provide
safety nets for cancer immunotherapists who may, at some point, want to dampen
down effective tumor vaccination protocols that threaten to become too aggressive
in the patient. Improved vaccination schedules may also be devised based on the
observed waxing/waning patterns of progression of autoimmune disease. Finally it
should eventually become possible to exploit analogous, but opposite, approaches
to those used in autoimmune therapy to enhance antitumor immune reactivity ±
such as [38] and [14] or [89] and [41].
In much the same way that not everybody develops autoimmune disease, so the success
of immunotherapy for different cancers will depend heavily on several factors:
(1) the histological type of the tumor and the range of antigens that it expresses,
(2) the individual tumor profile within that histological type and (3) the genetic constitution
of the individual patient. Perhaps there are certain combinations of tumors
and hosts for which there will never be a good match between immunizing antigens
and potentially reactive T cells. So it will be important to manage the expectations of
the clinical oncology community and raise the possibility that universally effective
immune therapies might not be an achievable goal.
Up to a certain point, the similarities between what those agents that trigger autoimmune
disease can achieve, and what tumor immunologists would like to achieve, coincide
very closely. The existence of autoimmune disease provides hope that immunotherapy
can be successful. Perhaps if these two fields of immunology combined
forces, e. g. through creation of interdisciplinary meetings and scientific collaborations,
we could not only learn how to induce potent antitumor immune responses,
but also how to prevent autoimmune disease by mimicking those mechanisms that