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

206 10 The Immune System in Cancer: If It Isn't Broken, Can We Fix It?
10.2
Evolutionary Tuning
The immune system has in place very sophisticated mechanisms to avoid recognizing
self antigens, through thymic T cell deletion and the generation of immunological
tolerance (see Box 10.1). The question then arises as to how good can it ever be at
recognizing the altered self antigens that arise from tumorigenic mutations (see below)?
If the immune system did no immunoediting [1, 2], the number of oncogenic mutations
that would be tolerated within tumor cells might be much greater than the repertoire
that is currently observed (Fig. 10.2). This would allow cellular transformation
to occur much more quickly and cancer would become a disease of early life. If
individuals routinely died of cancer before reproductive efficiency was maximal, the
evolution of enhanced immune mechanisms that recognize tumor-associated mutations
would provide an enormous selective advantage (Figs. 10.1 and 10.2).
Therefore, we would expect some degree of ªimmunoeditingº of tumors to occur; in
other words, the immune system would attack and destroy cells expressing mutant
proteins whose structures are sufficiently different from wild-type that they are no
longer recognized as self. Is there any evidence for this? Recently, Shankaran et al.
provided elegant proof that the growth of spontaneously arising tumors in immunocompetent
mice is indeed edited by the immune system [2]. These authors used
mice in which specific subsets of immune cells were genetically deleted. They
showed that both transplantable and spontaneously arising tumors grow more rapidly
in animals deficient in certain immune effector pathways than in animals
where the immune system is intact, indicating that highly immunogenic tumor-associated
mutations arise in the absence of a functional immune system. These animal
studies are consistent with observations that the oncogenic mutations seen in
clinically apparent human cancer cells are often very subtle, e. g. single amino acid
changes in oncoproteins such as Ras and Myc. This probably represents selection of
those mutations that do not per se give rise to immunogenic epitopes (see Appendix).
A prediction of this hypothesis is that there might be a much broader range of mutations
in cellular proto-oncogenes/tumor-suppressor genes that can promote uncontrolled
cellular proliferation but that are never actually seen in human cancer cells
because they are immunoedited out (Fig. 10.2C and D) [2]. This theory can now be
tested by analyzing the spontaneous tumors that arise in immunodeficient mice.
Are the apparently tight restraints that are placed oncogenic mutations that arise in
immunocompetent animals relieved in tumors growing in immunodeficient animals?
Experiments along these lines should help to establish whether the immune
system is a prime driver of selection of tumor genotype.
In summary, neither immune hypersensitivity nor immune ignorance to tumors
(Fig. 10.1) is likely to be the most beneficial situation to have evolved within the context
of the other competing commitments that the immune system has to keep.
However, immunoediting [2] of gross mutations in transforming oncoproteins
would provide a `third way' ± one that provides a delaying tactic so that most individuals
can pass their genes on to their progeny before dying of cancer. There is also