In the theory, anti-tumor immunity in invertebrates
might be based solely on the activity of the innate
immune system, relatively poorly developed network
of molecular mediators, a small number of effector
cells and proportionally poorly developed mechanisms
regulating immune response. Therefore, one of the
primary tasks of comparative tumor immunology may
be the identification of mechanisms of anti-tumor
immunity in invertebrates and comparing them with
their counterparts in vertebrates. On the other hand, all
vertebrates are characterized by both innate and
adaptive immunity, displaying great differences
related to the advancement stage of the adaptive
immunity, its correspondence with innate immunity. In
addition, differences in the mechanisms controlling the
immune reaction, number of cytokines and their role in
the immune response are also important. The
identification and comparative analysis of the
foregoing mechanisms in invertebrates and vertebrate
classes may contribute significantly in clarifying the
mechanisms of anti-tumor immunity failure in
mammals, as well as tracing the possible link between
these and immunoreproductive mechanisms.
Furthermore, this could be a way of introducing new,
more effective adjuvant and/or immunotherapeutic
procedures [4,11].
Based on recent findings, several mechanisms
have been identified that participate in the
development of the phenomenon of anti-tumor
immunity failure in vertebrates:
1. The processes of embryogenesis and
mechanisms establishing central immune tolerance to
"self" molecules are similar across all vertebrate
classes. Therefore, the mechanisms of
immunotolerance to embryonic and/or embryonic-like
tissues, such as tumor tissues, may be connected with
central immunotolerance [11,12]. There is evidence that
the mechanisms of central immunotolerance are, more
or less, active in adults. This phenomenon could also
be involved to some extent in the development of antitumor
immunity failure [12,13];
3. The mechanisms of peripheral maturation of
lymphocytes and possible influence of these on the
quality of the immune reaction have been also verified
in most vertebrate classes [13];
4. The immune system of vertebrates is closely
connected with auto-immunity being a by-product of
the adaptive immunity. "Self"-protective immune
reaction control mechanisms that could become
activated in anti-tumor immune reaction, co-evolved
alongside auto-immunity as a "new" evolutionary
phenomenon and a new form of selection pressure.
Therefore, the activation of anti-tumor immunity as a
unique form of auto-immune process was probably
followed by a parallel activation of protective
mechanisms, i.e. the immune reaction control
mechanisms [4];
5. Unlike non-mammals, the immune system of
mammals has "built-in" the mechanisms of tolerance
to proliferative tissues like trophoblast. These
mechanisms have developed, in the course of
evolution, under a very strong selection pressure of
alloimmunity and reproductive efficacy. Although
very similar to the mechanisms resembling autoimmunity,
the mechanisms of immune tolerance to
trophoblast can be regarded as more advanced and
more effective. On the other hand, there is a great
similarity between the mechanisms of immune
tolerance to trophoblast and anti-tumor immunity
failure mechanisms. These two, apparently diverse
mechanisms may be regarded as a protective immune
cross-reaction against the proliferative tissues of
diametrically different origin [4,11].
All vertebrates are, more or less, susceptible to
carcinogenesis, depending on the sensitivity of their
DNA to the influence by various carcinogenic factors.
The phenomenon of anti-tumor immunity failure is
relatively easily verifiable in all vertebrate classes, due
to the similarities in organization and functioning of
their immune systems. The phenomenon of anti-tumor
immunity failure in non-mammals rests largely on the
mechanisms of central immune tolerance to embryonic
and/or embryonic-like cells and control mechanisms
resembling auto-immunity. However, the
diversification of the immune reaction control
mechanisms in mammals has again produced new
possibilities regarding tolerance to proliferative
tissues, i.e. trophoblast and tumors. Several
observations could be taken as a basis for the future
research in the field of comparative tumor genetics,
immunology and immunogenetics:
1. The expression of class I and class II
molecules, tissue distribution of the molecules and
level of polymorphism of class I and class II genes in
non-mammals and mammals are substantially
different. In most non-mammals, class II genes are
more polymorphic in relation to class I, while class I
genes are highly polymorphic in mammal genome.
Tissue distribution of class II molecules in mammals is
restricted on APCs, dendritic cells and B lymphocytes,
while non-mammals shows the phenomenon of poor
restricted or unrestricted tissue distribution of the class
II molecules [14,15].
2. In all non-mammalian classes of vertebrates
class I and class II genes are rambling through
genome, but LMP and TAP genes are highly
evolutionary conserved within class I region. In
mammals, class I and class II genes are clustered on
the same chromosome (except equine), but LMP and
TAP genes are conserved within class II region [16,17,18].
3. The transcription of class II/LMP/TAP genes
in mammals are controlled from same signals. The
absence of class II genes transcription signals lockout
antigens processing machinery and class I molecules
peptide presentation, as well as the activation of Th1
cells and adaptive immunity effectors actions [19,20]. In
non-mammals, antigen processing machinery is under
control of class I genes transcription, because class
I/LMP/TAP genes are closely connected on the same
chromosomal loci [16,17,18].
4. Anti-tumor immunity in non-mammalian
(except birds) vertebrates predominantly depend on
the innate immune system, while anti-tumor immunity
in mammals depend on the innate and adaptive
immune systems and their communication [21].
5. The specificity in expression and tissue
distribution of MHC genes, LMP and TAP genes
transcription control, as well as the communication
between native and adaptive immunity in nonmammalian
vertebrates qualifies a substantially
different cytokine network and immune reaction than
in mammals.
6. There is a possibility that malignant cells in
fishes, amphibians, reptiles and birds are more
susceptible to apoptosis than mammalian malignant
cells [22].
7. The high resistance on carcinogens induced
genetic changes is evidenced in some experiments
with lower vertebrates, leading to a conclusion that
DNA from lower vertebrates shows a high level of
resistance on carcinogenesis [2,22].
8. The complex and efficient mechanisms of
immune reaction control developed under the
evolutionary pressure of high polymorphism of class I
genes, auto-immunity and reproductive effectiveness
can be included in the mechanisms of anti-tumor
immunity failure in mammals.
9. Mammalian extended cytokine network can be
activated/deactivated by same or similar factors under
different conditions such as pregnancy and
malignancy. A small number of cytokines and poor
cytokine network are the characteristics of nonmammalian
vertebrates. For example, cytokines like
IL-10 and IL-4 are unknown in fishes and amphibians,
but TGF-β is evidenced in reptiles, birds and probably
in other non-mammalian classes [23,24].
10. Th-like cells are detected in reptiles and
amphibians [25], as well as Th and/or Th1-like cells in
birds [26], but mammals are single vertebrates which
have the advanced system of immune reaction control
established on Th1 and Th2 cells, and their balanced
activity. The absence or fractional awareness of Th2
model of immune reaction control probably
contributes in the strong anti-tumor immunity in nonmammalian
vertebrates.
11. Mammalians' immune system may be tolerant
to cancer cells because they are very similar to
trophoblast cells [11].
12. Sex hormones, steroids and other factors,
which are the attributes of pregnancy and malignant
processes, can impair blood-thymus barrier. It can be
another mechanism of acquired thymic tolerance to
foreign molecules in pregnancy and malignancy [12].
13. The absence of MHC and costimulatory
molecules expression, prostaglandine, Th2 cytokines,
sex hormones, steroids and other factors could be
promoter of extrathymic lymphocytes maturation in
antigen-protective manner in mammalians. It is yet
one of the mechanisms that are included in trophoblast
and tumor escape [13].
14. Unlike mammals, the mechanisms of immune
reaction control in non-mammalian vertebrates
probably are essentially independent from an
important role of co-stimulatory molecules. Actually,
co-stimulatory molecules like CD40, CD80, CD86 and
OX40 were not detected in non-mammalian
vertebrates, except CD80 and CD86-like molecules in
birds [27].
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