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

10.6 Exploiting Weaknesses: Autoimmunity
tors that determine ªthe overall reactivity and quality of cells of the immune systemº
[15]. Genetic linkages to autoimmune diseases [19] that affect genes involved in general
immunoreactivity [20] include genes encoding cytokines, molecules involved in
cell proliferation and inhibitors of apoptosis, as well as genes involved specifically in
antigen presentation and recognition [15, 21, 22]. For example, there is a strong genetic
contribution to the development of rheumatoid arthritis at various HLA-DR alleles
(especially HLA-DRB1*0401 and *0404 in Europeans [15, 21, 22]). These data
suggest that such individuals may be able to present epitopes from self-derived antigens
more effectively than other members of the population. If so, it may be that
cancer patients of particular haplotypes may be more capable of presenting self, or
near-self, epitopes derived from oncogenic mutations that arise in particular cancer
types. Such correlative studies are only in their infancy, but may provide the cancer
immunotherapy field with a rich resource in diagnostic information for the design
of cancer vaccine strategies on a patient-by-patient basis.
It has also been anecdotally reported that infections (usually with unknown agents)
are associated with the onset of many autoimmune diseases and the nature of the response
to infections can skew immune responses in directions that can promote
autoimmune development (Fig. 10.5A) [23]. In animal models of autoimmune disease,
the injection of adjuvants (see Appendix) is usually necessary [24] ± and sometimes
sufficient [25, 26] ± to induce the pathology. This is directly reminiscent of one
of the few truly successful immunotherapy treatments for cancer; thus, treatment of
bladder cancer can be effective by treatment with BCG which is believed to work by
acting as a powerful adjuvant to stimulate both non-specific and specific antitumor
immune effector cells to clear the tumor cell population. Thus, adjuvants can either
improve immune responses to unrelated self antigens (Fig. 10.5A) [27], promote
cross-reaction with autoantigens through molecular mimicry (see Appendix)
(Fig. 10.3) [28] or act to inhibit T cell death following activation and killing [29, 30].
These characteristics of autoimmune disease offer significant encouragement for
the development of tumor immunotherapies [31±35]. If self antigens exist in most
tissues that can be the targets of Tand B cell immune reactivity, cancers of most histological
types could potentially be targeted by immune responses if the appropriate
target antigens could be identified. The other side of the coin is clearly that there is a
concomitant danger of developing autoimmunity against the tissue from which the
tumor derives (see below). It might also be possible to exploit an understanding of
the genetic determinants of autoimmunity to tip the balance towards antitumor immune
reactivity (Fig. 10.3). In particular, genes affecting T cell recognition of peptides
(e.g. specific MHC haplotypes) are often central to the development of autoimmune
disease [15, 20, 22]. Finally, the mechanisms that promote the unintentional
turning of the immune system against self targets also means that it might be possible
to copy these mechanisms to enhance the immunogenicity of self or near-self tumor
antigens [23]. So, it might be possible to use the initiating agents for autoimmune
disease [24±27, 30] as adjuvants in immunotherapy. In addition, mimicry of
tumor antigens by other closely related antigens [36] from naturally occurring microorganisms
might, if they can be found, yield tumor antigen-specific vaccination strategies.
In addition, if the presumed infectious agent that initiates, for example, mul-
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