Foreword
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1. Cancer
1.1. Cancer – A Common Disease
1.2. What is Cancer?
1.3. Is there a Cure for Cancer?
2. Our Immune System – A Short
Overview
2.1. Innate and Adaptive Immunity
2.2. The Key Role of Macrophages in the Immune System
3. Cancer and the Immune System
3.1. The
Role of the Immune System in Cancer Defense
3.2. Cancer, Cell Death and the Immune System
3.3. Innate and Adaptive Immunity in Cancer
Defense
4. References
1. Cancer
1.1. Cancer – A Common Disease <
In
Fig. 1. Causes of mortality in
(Data Statistics
1. 2. What is Cancer? <
Cancer [W] is the uncontrolled multiplication and spread
of aberrant body cells and the ensuing destruction of the structure and function of essential organs. Cancer is a multicausal and
multifactorial disease, which is due to the loss of control over genetic stability, cell division [W], regulated cell death and the
tissue-anchorage of single cells in our body. The development of cancerous cells usually happens by gradual accumulation of genetic
damage on one hand and a complex interplay of local tissue factors on the other hand, which ultimately generate the framework for
the uncontrolled and invasive growth of a tumor. The genetic aberrations of cells may either be caused by direct substantial changes (mutation [W])
of single genes by chemical or physical influences (e.g. radiation), but also by so far less well understood changes in the expression
patterns of single genes (so-called epigenetic changes [W]). Finally, also viruses [W], to a so far probably underestimated extent,
are involved in the development of cancer cells, for instance via shutdown of control mechanisms that safeguard the genetic integrity
of our cells, but also via direct influence on the control mechanisms of cell division and cell death or via direct mutations.
Thus,
factors in our immediate environment are the key determinants causing the development of cancer cells. Besides, there is also a genetic
susceptibility for such aberrations of body cells, e.g. as a consequence of inherited defects in the repair mechanisms for mutations.
Despite such genetic “predispositions“ however, as impressively proven by a large number of epidemiologic studies on the regional
incidence of cancer, the “external“ influences are by far dominant [4], with one very prominent external factor being our diet [5].
In
addition to these external influences that may cause mutations of body cells, to result in cancer, typically also certain conditions
in the surrounding tissue of aberrant cells must be fulfilled to allow for the unrestricted growth of cancer cells. In this respect,
especially growth stimuli, e.g. as a consequence of tissue damage and the ensuing healing processes, are of critical importance. In
particular, chronic inflammation and the associated chronic healing processes play a key role in the development and spread of cancer [6].
If
eventually all these conditions are met, single aberrant body cells may generate larger, still locally restricted cell masses (tumors [W])
and in worst case, via migration of cancer cells, also distant sites of tumor growth disseminated all over the body (metastases [W]).
In general, this constitutes an irreversible step, which by destruction of vital organs typically results in the rather rapid death
of the patient.
1. 3. Is there a Cure for Cancer? <
In contrast to the, in view of the described situation, widespread notion that
cancer is incurable anyway, medical statistics proves that nearly half of all cancer cases, with respect to normal lifespan, do not
ultimately cause death of afflicted patients. Based on numbers, this is not equal to effective cure, yet, the long-term survival of
cancer patients suggests that at least long-term control of the disease is possible in principle. Furthermore, the rare, but repeatedly
documented cases of spontaneous cancer cures imply that our body in principle is capable of completely eradicating cancer cells, or
at least controlling them throughout lifetime (more in [7]). The key to this is held by our immune system.
2. Our Immune System – A
Short Overview [8]
2.1. Innate and Adaptive Immunity <
Humans, like all other higher vertebrates, harbour an immune system [W], which
primarily serves to guard us against infections. This defense system, which in terms of complexity can only be compared with the nervous
system, consists of a whole set of highly specialized cell types, whose controlled interplay accounts for our daily survival. In fact,
without our immune system we would succumb within a few days to primarily bacterial infections.
In principle, our immune system consists
of a developmentally ancient part, which is responsible for the so-called “innate“ or “nonspecific“ immunity [W], and a more recent
part, which is responsible for the so-called “adaptive“ meaning flexible immune response [W] (see schematic representation in Fig.
2).
Fig. 2. Schematic representation of the immune system and the most important immune cell types (see text).
(©
G. Schwamberger)
These two systems do not act independently of each other, but are interconnected by a multitude of signals,
mediated by messenger molecules (so-called cytokines) [W] or cell surface molecules, to bring about a rapid and efficient defense
reaction. The key role as a mediator between the two arms of the immune system is held by the so-called dendritic cells [W], since
they ultimately “decide”, which structures will be recognized by the adaptive system as being “dangerous” and therefore are to be
destroyed.
In functional terms, the systems of “innate“ and “adaptive” defense differ from each other in several aspects:
The innate
part of our immune response is mostly based on three different cell types, the phagocytes (granulocytes [W] and macrophages [W]) and
the natural killer (NK) cells [W]. While the former primarily serve to rapidly eradicate invading microbes (bacteria and fungi), NK
cells act as a first barrier against the spread of viral infections by recognizing virally infected cells and destroying them. Critical
for our survival is in both cases the almost immediate defensive capacity of the system. To achieve this, the innate immune response
uses an ancient, comparatively simple recognition system, which is based on evolutionary conserved structures of microorganisms on
one hand, and on stress molecules in case of infected body cells on the other hand. In most cases of subliminal infections, this system
is in itself capable of warding off the pathogen and to block its dissemination throughout the body. The disadvantage of this system
however is that each new confrontation with a given pathogen triggers the same reaction pattern, i.e. the system does not remember
or only remembers short term. In view of our lifelong coexistence with certain pathogens, this does not constitute an “ideal solution“.
Because
of this, with the adaptive part of the immune system, nature has created a sort of memorizing “turbo defense system“. This consists
of two, or more precisely, three cell types out of the class of lymphocytes, the so-called B cells [W] and the T cells [W], the latter
being divided into so-called helper T cells [W] and killer T cells [W]. In contrast to the innate part of the immune system, B and
T cells are capable of recognizing nearly any possible structure and mount a defensive reaction against this structure, the so-called antigen [W].
This is achieved by an enormous diversity of structurally modified receptor molecules, which is generated by modification of the respective
genes during the development of these cells. For this, it is of critical importance that each of these cells harbours only its characteristic
genuine antigen receptor. If an antigen now binds to such a receptor, the respective immune cell gets activated. This, on one hand,
causes the dramatic proliferation of the cell(s) specific for the respective antigen, on the other hand, these cells contribute in
various ways to the destruction and disposal of the antigen-bearing structures (e.g. bacteria or viruses). This includes the production
of antibodies [W] by activated B cells, which mark antigens for uptake by macrophages, or the direct destruction of infected body
cells by activated killer T cells. In contrast, the task of helper T cells is primarily to support the activation of B cells and killer
T cells. In addition, helper T cells in turn also activate the cells of the innate immune system, ultimately resulting in a coordinated
defense reaction against invading pathogens.
Yet, also the adaptive immune system has a crucial disadvantage. It is by far too slow.
Thus, the induction of an effective T cell response takes 5 to 7 days, while effective protection by antibodies, produced by B cells,
may require up to 14 days. If we would be solely dependent on these adaptive defense reactions, we would simply not exist. This time
gap is again closed by the innate defense system with its broad-banded but extremely rapid defense reaction. Thus, it is not surprising
that the largest part of the animal kingdom, with exception of the vertebrates, gets along without the adaptive part of the immune
system, whereas any animal organism harbours an innate defense system. Nonetheless, the “luxury“ of an additional, adaptive immune
system has a decisive advantage, namely the “immunological memory“. Because after each activation of an antigen-specific B or T cell,
correspondent “memory cells“ are put aside, which, on contact with their specific antigen, get activated considerably faster, and
thus close the time gap more rapidly. It is this principle, prophylactic vaccinations are based on. They provide the immune system
with a head start of several days, which may constitute the crucial difference between survival and death.
2.2. The Key Role of Macrophages
in the Immune System <
Macrophages, in developmental terms, are the most ancient cells of our immune system and in all multicellular
animal organisms constitute the most simple form of an immune system. Their function is primarily the uptake and destruction of all
kinds of foreign matter, a reaction termed phagocytosis [W], to which these cells owe their discovery by Ilya Metchnikoff [W] and
the term macrophages (= big eaters) (Fig. 3).
Fig. 3. Microscopic picture of the phagocytosis of yeast particles
by macrophages.
Left: Macrophages and lymphocytes in cell culture, immediately after addition of yeast particles (H). Right: 2 hours
after addition of yeast particles, the particles have been almost completely ingested by macrophages.
(© G. Schwamberger)
In fact,
macrophages constitute a highly effective, and in a certain sense largely autonomous defense system, that has remained the only defense
system against invading microbes for many animal organisms. Thus, it is no surprise that also in vertebrates, these cells can be found
in all tissues and organs, where they act as the first, immediate line of defense against the invasion of microorganisms. By this,
macrophages also play the key role for recognition of potentially dangerous intruders. Once this has happened, the foreign structure
is taken up within minutes and destroyed. At the same time, this reaction also causes a still local activation of these cells, which
in turn attracts and activates more neighbouring macrophages. In most cases, this is sufficient to complete the defense reaction,
without ever being noticed. In case of a more wide-spread infection, e.g. as a consequence of a severe injury, however, a more far
reaching reaction ensues, which results in the recruitment and activation of further immune cells from the blood stream and a more
intense and now quite perceptible defense reaction termed inflammation [W] (Fig. 4).
Fig. 4. Schematic representation
of the key role of macrophages as danger sensors of the immune system (see text).
(© G. Schwamberger)
At this point, a further
critical reaction for our defense takes place. Macrophages, and the closely related dendritic cells, present fragments of the ingested
structures on their surface, and by this enable the recognition of these structures by helper T cells, which in turn is crucial for
induction of the whole adaptive immune response. Whether this antigen presentation [W] is productive, or instead leads to immunological
tolerance [W], meaning the permanent switching-off of an immune response, primarily depends on the reaction of the presenting cells
towards these structures, namely whether these structures constitute a potential danger for the organism. This is true for a multitude
of microbial structures, which signal an infection to the immune system, but also for damaged endogenous structures, as in case of
an injury.
Why such an incredibly complicated system? Since the adaptive part of the immune system, as already mentioned, may in principle
recognize any arbitrary structure, irrespective of being foreign or self, as an antigen, we need an additional selection system to
avoid unnecessary and, above all, dangerous defense reactions against harmless or self structures. Thus, in this way, the adaptive
immune system “learns” to distinguish between dangerous intruders and its own organism, based on the recognition reactions of the
innate defense system. If this learning process is defective, this, on one hand, leads to a suppressed defense reaction, as in the
case of chronic infections, or, on the other hand, to defense reactions against self structures (autoimmunity [W]), as e.g. in case
of rheumatoid arthritis [W] or multiple sclerosis [W].
Thus, the control of macrophage activation is a life-long act of balance, which
is essential to our survival and is further complicated by the fact that macrophages also perform vital functions outside the immune
system. In fact, these cells are responsible for many aspects of normal tissue architecture, as e.g. the setup of the blood vessel
supply, the removal of dead body cells, as well as the normal restructuring of tissues in the context of regenerative processes or
after injuries. In a way, macrophages might be compared to an army that, in the absence of threats from the outside, is used for constructive
“civil” tasks, and in this case without armament. Because actually, the defense-oriented and the constructive tasks of these cells
are separated from each other by a complex network of signals and feedback loops, i.e. the cells, depending on the nature of the inducing
signals, may either perform one or the other set of functions (Fig. 5).
Fig. 5. Schematic representation of the dual
role of macrophages in immune defense and tissue regeneration (see text).
(© G. Schwamberger)
It is just this conflict of tasks
that is crucial for the growth of a tumor or its timely destruction.
3. Cancer and the Immune System
3.1. The Role of the Immune Systems
in Cancer Defense <
Besides its central function in the defense against infections, the immune system also constitutes one of our
most important safeguarding mechanisms against cancer. With respect to this immune surveillance, the cells of the innate part of the
immune system, in particular macrophages and NK cells, are of crucial importance for the timely recognition and removal of cancerous
cells [9], whereas the adaptive part of the immune system comes into effect only as a second line. Thus, NK cells and appropriately
activated macrophages are able to recognize a wide variety of cancer cells via specific stress molecules at the latter’s surface [10] and
subsequently destroy these cells in a selective manner (Fig. 6). This reaction most likely constitutes our most important and usually
highly effective safeguarding mechanism against cancer cells, continuously arising as a consequence of external influences.
Fig.
6. Microscopic picture of the destruction of cancer cells by macrophages.
Left: Clusters of growing cancer cells (T, unstained) next
to unstimulated macrophages (M, stained red). Right: Remnants (cell nuclei) of destroyed cancer cells (T, stained dark blue) next
to activated macrophages (M, stained red).
(© G. Schwamberger)
The actual efficiency of this immune surveillance however largely depends
on the activation status of the respective immune cells, meaning that, dependent on endogenous and exogenous influences, also this
safeguarding mechanism does not render us completely immune against cancer. To better understand this aspect, we need to shed some
more light on the interplay of the immune system, particularly macrophages, and cancer.
As already mentioned, macrophages lead a sort
of dual life and, dependent on the local conditions in a given tissue, may take over two diametrically opposing tasks. In addition,
the activity of macrophages is also influenced by higher-level factors, acting on the whole organism. Thus, a multitude of influences
exist, that modulate the polarization of macrophages in one way or the other. As examples for positive, i.e. defense-supporting influences,
physical exercise, certain vitamins, but also an increase of body temperature (e.g. fever) should be mentioned, whereas for instance
chronic stress, lack of sleep, lack of daylight or also a reduction of body temperature have a negative impact on the defense capacity
of macrophages. Also our hygiene, our diet and various environmental toxins affect the activity of this defense system in a complex
fashion.
In case of a prolonged disturbance of the balance to the disadvantage of the defense functions, cancer cells may escape this
immune surveillance and rather rapidly establish a still small tumor focus. At the same time, macrophages are actively recruited into
such growing tumor sites, where, in certain cases, they may constitute up to 50 % of the total cell mass. Paradoxically however, there
they also constitute the most important cells for the rapid and unrestricted growth of the tumor. This obvious contradiction is explained
by the ambivalent function of macrophages and the responsible signals. A growing tumor in many aspects resembles a mixture of chronic
inflammatory and healing processes, which, in the absence of external danger signals, leads to a polarisation of macrophages towards
tissue-supportive functions, especially towards generation of new blood vessels, supplying the tumor with oxygen and nutrients, and
by this enabling the growth of the tumor in the first place. Thus, macrophages become repolarized by a growing tumor and abused for
its benefit [11].
This circumstance has recently led to the somewhat single-sided view of macrophages as being cancer-promoting “culprits“.
Yet, at the same time, appropriate activation provided, these cells are able to destroy the tumor within a short span of time [12].
Furthermore, appropriate activation of macrophages and dendritic cells is also the basis for induction of a downstream adaptive immune
reaction against the tumor, which in a way represents a natural vaccination against the tumor, and is crucial for the eradication
of remaining metastases and protection against relapse. Thus, as in case of infections, activation of the innate defense functions
of macrophages against tumors represents the key to a successful immune defense against cancer.
3.2. Cancer, Cell Death and the Immune
System <
This last point requires one important amendment. Since our immune system primarily serves to recognize and destroy invading
foreign organisms, while at the same time trying to avoid damage to body structures as far as possible, the immune system is faced
with the problem that cancer cells after all are self, albeit altered body cells and for this reason should be subject to immunological
tolerance. And despite altered structures, this in fact holds true in the majority of cases. How can the (adaptive) immune system
nevertheless distinguish cancer cells from normal cells? As already mentioned, NK cells and macrophages recognize cancer cells primarily
based on stress molecules on the latter’s surface. The presence of these molecules is a consequence of the misdirected biological
processes in the cancer cells and signals the immune surveillance that these cells constitute a hazard and thus have to be eliminated.
This principle also explains, why particularly macrophages are able to recognize and destroy a wide variety of unrelated cancer cells.
Why
then do cancer cells escape from immune surveillance?
Besides the already mentioned influences of the local tissue milieu that may
lead to a suppression of immune surveillance, the key to this paradoxically lies in the danger potential of dead cells. How can a
dead cell constitute a hazard after all? For this, one has to realize that our organism consists of about 100 trillions (1014) tightly
packed cells. Every day, about 10 billions (1010) of these cells (this is about 0.01 % of the total number) die and have to be replaced
by neighbouring cells. To make this possible however, the dead cells have to be disposed of first. And importantly, this has to happen
before their cellular contents gets spilled and damages the surrounding tissue. To ensure this, nature has developed the mechanism
of programmed cell death (apoptosis) [W]. This leads to an active and ordered disintegration of aged or damaged cells. At the same
time, molecules emerge at the surface of these cells, which signal to neighbouring macrophages that the remnants of these cells have
to be cleared. Originally, it was assumed that this process happens silently, i.e. without further consequences. This however turned
out to be an erroneous belief, since in fact the “eat me“ signal molecules present on the surface of apoptotic cells cause a repolarization
of macrophages towards tissue supportive functions [13], which in principle of course makes sense. At the same time however, as already
mentioned before, this leads to a suppression of the defensive functions of macrophages [14], which in case of cancer cells obviously
is fatal. And even more so, because with this polarization also the activation of the adaptive immune defense against cancer cells
by T cells fails to happen and the program of the immune system instead switches to active tolerance. By this, the local immune surveillance
by macrophages and NK cells gets actively suppressed, which finally relieves the developing tumor from immunological control. The
immune system has turned blind towards the cancer cells.
How do apoptotic cancer cells arise?
Normally, programmed cell death is subject
to multifaceted controls, checking the orderly function of the respective cells, especially concerning genetic integrity and the execution
of cell division. If any disturbances or signal conflicts arise, the “suicide program“ of apoptosis is triggered for safety reasons.
Such disturbances are particularly common in abnormal cells, resulting in a high spontaneous disposition towards apoptosis especially
in early cancer cells. In this sense, developing cancer sites are at the same time sites of abnormal cell division activity and also
enhanced apoptosis. But also methods of conventional cancer treatment, like chemo- and radiotherapy, frequently trigger programmed
death of cancer cells by damaging cellular structures, which, besides general impairment of the immune system, further undermines
immune defense against cancer cells.
Are there ways out of this vicious circle?
The way out of this dilemma can be found within the
mechanisms of the immune system itself. Whereas the natural death of cells in the organism as a rule happens via the apoptotic pathway,
body cells recognized as being dangerous by the immune system are being destroyed in a non-apoptotic fashion [15]. This form of cell
death, known as necrotic cell death [W], under normal circumstances primarily happens as a consequence of tissue injury. In contrast
to apoptosis, it results in the rapid, uncontrolled demise of the affected cells. This in turn, via recognition of intracellular structures
of the destroyed cells by macrophages and dendritic cells, leads to activation of these cells and other immune cells and an enforced
defense reaction [14], which finally causes the triggering of an adaptive immune response against altered or novel structures of the
destroyed cells [16] (Fig. 7).
Fig. 7. Schematic representation of the consequences of the mode of cell death of
cancer cells for cancer immune defense (see text).
(© G. Schwamberger)
Thus, the immune system fundamentally differentiates between
orderly dying body cells, and those dying as a consequence of injury or active destruction by the immune system. This mechanism is
ultimately crucial for the functioning of our immune system and the balance between active immunity against e.g. viruses or also altered
structures of cancer cells, so-called tumor antigens [W], and the maintenance of tolerance towards our normal body cells. Because,
if the immune system would destroy dangerous cells in an apoptotic fashion, it simply would block its downstream activity via induction
of tolerance. This however also means that the decision about an adaptive immune response against altered structures of body cells
already happens at the level of the innate immune reaction. Consequentially it follows that the best prerequisite for building a stable
adaptive immune response against tumor structures is the prior recognition and destruction of tumor cells by the innate defense system.
3.3.
Innate and Adaptive Immunity in Cancer Defense <
So, what is the practical role of adaptive versus the innate immunity in cancer
defense? In view of the tight interrelationship of both systems, this question cannot always be answered unambiguously. But as discussed
before, adaptive immunity always constitutes a delayed amplification mechanism of innate immunity, with the “bonus“ of a life-long
memory. Particularly the latter, without any doubt, constitutes an important safeguarding mechanism against remaining so-called “sleeping“
cancer cells and metastases. On the other hand, the specific recognition of tumor antigens is the biggest Achilles heel of this system,
since cancer cells, due to their high genetic instability, very often lose these structures over time and thus are not recognizable
anymore by the defense mechanisms of adaptive immunity [17]. Based on various studies, this may be true for almost two thirds of all
cancer cells studied [18]. Furthermore, not all types of cancer cells do harbour recognizable tumor antigens, and thus are not recognized
as such by the adaptive immune system.
In contrast, the stress molecule-based recognition of cancer cells by the innate immune system
is substantially more reliable. Particularly, activated macrophages are able to recognize and destroy almost all known types of tumor
cells, and subsequently, as far as possible, initiate an adaptive immune response. So, without doubt, the innate immune system takes
the lead part in natural cancer defense. Thus, understanding the underlying molecular and cell biological mechanisms of this defense
reaction constitutes a fundamental key to the development of scientifically founded biologic therapies for cancer.
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