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The fallacy of tumor immunology: Evolutionary pressures, viruses as nature's genetic engineering tools and T cell surveillance emergence for purging nascent selfish cells

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The US and Hungarian statistical records of the years 1900 and 1896, respectively, before the dramatic medical advances, show 32% and 27% deaths attributable to infections, whereas only 5% and 2% due to cancer. These data can be interpreted to mean that (i) the immune system evolved for purging nascent selfish cells, which establish natural chimerism littering the soma and the germline by conspecific alien cells and (ii) defense against pathogens that represent xenogeneic aliens appeared later in evolution. `Liberating' T cells from the semantic trap of immunity and the shackles of the `two-signal' model of T cell activation, we point out theoretical grounds that the immune response to cancer is conceptually different from the immune response to infection. We argue for a one-signal model (with stochastic influences) as the explanation for T cell activation in preference to the widely accepted two-signal model of co-stimulation. Convincing evidence for our one-signal model emerged from the widespread autoimmune adverse events in 64.2% of advanced melanoma patients treated with the anti-CTLA-4 antibody (ipilimumab) that blocks an immune checkpoint. Harnessing the unleashed autoimmune power of T cells could be rewarding to defeat cancer. Assuming that immunization against isogeneic tumors also would be effective is a fallacy.
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Bakacs et al. Viruses as nature’s genetic engineering tools January 11th 2016
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The fallacy of tumor immunology
Evolutionary pressures, viruses as nature’s genetic engineering tools and T cell surveillance
emergence for purging nascent selfish cells
Tibor Bakacs1, MD, DSc, Katalin Kristóf2, MD, PhD, Jitendra Mehrishi3, PhD (Cantab),
FRCPath, Tamas Szabados4, PhD, Csaba Kerepesi5, PhD, Enikoe Regoes6, PhD, and
Gabor Tusnady1, PhD, DSc
1Department of Probability, Alfred Renyi Institute of Mathematics, The Hungarian Academy of
Sciences, 1053 Budapest, Reáltanoda str. 13-15. Hungary; 2Department of Anesthesiology,
Emergency and Intensive Care Medicine, University of Göttingen, Robert-Koch-Str. 40,
Göttingen, 37075, Germany; 3The Cambridge Stem Cell-Gene Therapy, Cultivated RBC
Research Initiative
1
; 4Department of Mathematics, Budapest University of Technology and
Economics, Műegyetem rkp 3, Budapest, 1521, Hungary; 5Department of Computer Science,
Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117 Budapest, Hungary;
6European Laboratory for Particle Physics (CERN) Geneva 23 CH-1211 CH-1211,
Switzerland.
e-mail addresses: tiborbakacs@gmail.com (TB), katalin.kristof@med.uni-goettingen.de (KK),
stemcell-crbc@virginmedia.com (JM), szabados@math.bme.hu (TSz),
kerepesi@caesar.elte.hu (CsK), Enikoe.Regoes@cern.ch (ER),
tusnady.gabor@renyi.mta.hu (GT).
Running title: Viruses as nature’s genetic engineering tools
Keywords: cancer deaths; infectious disease deaths; individual integrity; one-signal T cell
model; ipilimumab; harnessing autoimmune T cells; fallacy of tumor immunology.
MS pages: 15; text words: 3820; text characters with spaces: 26231; Figure: 1.
It is not the strongest of the species that survives, nor the most intelligent, but the one most
responsive to change.” Charles Darwin
Summary
The US and Hungarian statistical records of the years 1900 and1896, respectively, before
the dramatic medical advances, show 32% and 27% deaths attributable to infections,
whereas only 5% and 2% due to cancer. These data can be interpreted to mean that (i) the
immune system evolved for purging nascent selfish cells, which establish natural chimerism
1
Dr J N Mehrishi was formerly an Assistant Director of Research in the University of Cambridge, Department of
Radiotherapeutics and a Research worker in the Department of Medicine. After leaving the University JNM for
continuing studies and cooperation with international collaborators launched the Research Initiative
(Independent of and separate from the University of Cambridge).
Bakacs et al. Viruses as nature’s genetic engineering tools January 11th 2016
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littering the soma and the germline by conspecific alien cells and (ii) defense against
pathogens that represent xenogeneic aliens appeared later in evolution.
‘Liberating’ T cells from the semantic trap of immunity and the shackles of the ‘two-signal’
model of T cell activation, we point out theoretical grounds that the immune response to
cancer is conceptually different from the immune response to infection. We argue for a one-
signal model (with stochastic influences) as the explanation for T cell activation in
preference to the widely accepted two-signal model of co-stimulation. Convincing evidence
for our one-signal model emerged from the widespread autoimmune adverse events in
64.2% of advanced melanoma patients treated with the anti-CTLA-4 antibody (ipilimumab)
that blocks an immune checkpoint. Harnessing the unleashed autoimmune power of T cells
could be rewarding to defeat cancer. Assuming that immunization against isogeneic tumors
also would be effective is a fallacy. (201 words)
Significance
Immunotherapy trials conducted with the best available science so far have not quite fulfilled
the great hopes of conquering cancer. Most spontaneous tumors are a part of self, a unique
invention of nature. Nearly all neoantigens represent “passenger” mutations that do not
directly contribute to tumorigenesis. The autoimmune power of T cells unleashed by immune
checkpoint blockade should be harnessed for curing cancer. Assuming that immunization
against isogenic tumours should also be successful to defeat cancer in a manner similar to
xenogeneic infections is a fallacy. (86 words)
Introduction
Alfred Tauber proposed that “…’immunity’ may be a semantic trap that has confined
our understanding of the immune system to only a narrow segment of defensive, aggressive
functions” (1). In fact, Macfarlane Burnet suggested first to regard the evolutionary origin of
adaptive immunity as being related to something other than defense against pathogenic
microorganisms (2). Unanswered questions like why invertebrates including more than two
million species in more than 20 phyla use only germline encoded innate immunity, or why
vertebrates reject any allogeneic or xenogeneic transplanted tissue inspired Rinkevich to
challenge the tacit assumptions based dogma that evolution of the immune system is
pathogenically directed (3). Instead, he proposed that immunity developed as a surveillance
operation to purge nascent selfish cells. Such cells could be isogeneic tumors from the host
or transmissible allogeneic cells from kin organisms establishing natural chimerism littering
the soma and the germline by conspecific alien cells. According to Rinkevich the primary role
of the vertebrate immune defense is to combat these parasitic events and preserve the
Bakacs et al. Viruses as nature’s genetic engineering tools January 11th 2016
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individual homogeneity. Somatic compatibility systems that deter genotypes from being
contaminated by maladapted alien genotypes might be the origin of immunity (4). Defense
against pathogens, which are xenogeneic aliens appeared later in evolution.
Some current examples of parasitic allogeneic cells are instructive. Canine
transmissible venereal tumor (CTVT) is a transmissible cancer allograft that rapidly spreads
naturally in dogs worldwide (5). CTVT may have first arisen within a genetically isolated
population of early dogs whose limited genetic diversity facilitated the escape of cancer from
the immune surveillance system of the host. The Tasmanian devil facial tumor disease
(DFTD) is another highly aggressive cancer allograft presenting a serious extinction risk for
the Tasmanian devil population (6). DFTD arose in an island population with low genetic
diversity. It seems that populations with limited genetic diversity may be particularly
susceptible to the emergence and spread of transmissible cancers. This way, transmissible
allogeneic tumors might have contributed to the evolutionary force shaping the class I
immune surveillance system (7).
Based on the complementarity theorem of Dillon and Root-Bernstein (8) (9), we
proposed that individual integrity can be preserved from parasitism with a limited repertoire.
This is achieved by a homeostatic coupled system via internal dialogue between the
positively selected, low affinity complementary T cells and host cells (10) (11). The role of
regulatory T Cells (Foxp3+ Tregs) seems to be the closest analogy to the role of homeostatic
T cells in our model, which is described in more details in (11).
The thrust of this paper is a fresh approach to reconsider the evolutionary role of
viruses with respect to cancer over millions of years for adaptation and survival. The viruses
are not just hostile invaders, but the molecular biologic tools of Nature’s genetic engineering
laboratory that have been influencing and regulating key aspects of our biology (12).
Following Tauber, we liberate T cells from the semantic trap of immunity and suggest
that the primary function of T cells is to prevent dedifferentiation that is, “…in a world in
which necessity is represented by an inevitable disappearance of differentiation.”
2
This way,
T cells put strict limits on variations of host cells and prevent a natural tendency of people to
develop tumors.
Unexpectedly, the first robust vindication for this proposal emerged from the
widespread autoimmune adverse events in advanced melanoma patients receiving the
checkpoint blocking anti-CTLA-4 antibody (ipilimumab) (13) as described below.
1. Ipilimumab clinical trials Our alternative interpretation of severe, widespread
autoimmune-related adverse events
2
Quoted from Norbert Wiener: I Am a Mathematician
Bakacs et al. Viruses as nature’s genetic engineering tools January 11th 2016
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The developers of the inhibitory anti-CTLA-4 antibody, ipilimumab, started with the premise
that in an individual with no pathology other than cancer, most CTLA-4 expressing T-cells are
either effector cells engaged in an anti-tumor response or regulatory T-cells actively
opposing that response (14). Therefore, a CTLA-4 blockade would then selectively target T
cells involved in the anti-tumor immune response. Although ipilimumab improved survival in a
minority of metastatic melanoma patients, the vast majority suffered autoimmune-related
adverse events (irAEs). The data from 14 completed phase IIII trials of ipilimumab indicated
that irAEs occurred in 64.2% of patients. Life-threatening side effects, pathognomonic of
acute graft-versus-host-disease (GVHD) and drug-related deaths (<0.1%) have been
reported in most trials (15) (16). Notwithstanding, for some obscure reason, the CTLA-4
blockade is persistently thought to be tumor specific.
We are inclined to suggest a cautious view that the widespread and dose-dependent
irAEs of ipilimumab can be better explained by our one-signal T cell activation theory (11)
(17) (18) (19) (20) than by the conventional two-signal T cell activation models. Our model
suggests that all T cells are temporarily activated, expressing CTLA-4 that can then be
targeted by anti-CTLA-4 antibodies. This is consistent with the immunological homunculus
concept of Irun Cohen, who suggested that the immune system continuously responds to self
(21) (22) (23) (24). Evolution may give an answer as to why such constant self peptide
control is necessary.
2. Viruses playing a pivotal role in evolution may increase the risk of DNA damage and
cancer
Viral genes outnumber cellular ones in the biosphere. The delivery of genes from virus to cell
being invaded is far more overwhelming when compared with the reverse event, i.e. transfer
of genes from host cells to viruses. Thus, viruses, apart from altering the cell surface
molecular complex, the arena of specific interactions (25) (26) (27), have the unique ability to
alter hundreds of genes with minimal genomic burden. Microarray analysis of transduced
CD34+ cells with the GFP lentiviral vector revealed that a total of 513 genes were altered in
terms of expression. Out of these, 183 (35.2%) were upregulated more than twofold while
330 genes (64.4%) were downregulated (28).
It had been proposed (12) that ancient viruses in evolution have spontaneously acted
as essential editors of the host genome. This way, viruses may be thought of as the
molecular biologic tools of Nature’s genetic engineering laboratory” able to manipulate key
aspects of our biology. Such natural genetic engineering in evolution will have contributed to
the emergence of evolutionary innovations. A recent analysis confirmed that horizontal gene
transfer is a hallmark of animal genome, although awareness of this virus-host ecology was
not a part of the original Darwinian Theory (29) (30) (31) (32) (33) (34) (35).
Bakacs et al. Viruses as nature’s genetic engineering tools January 11th 2016
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Natural genetic engineering mediated by viruses is a double-edged sword. Whereas
viral gene transfer speeded up the evolution of the species, viral remnants, e.g. jumping
genes, represented a real danger to the individual by increasing the risk of DNA damage,
cancer, and other maladies. Genomes with various interactions occurring are likely to be
hotbeds of evolutionary conflict.
3
Epidemiological observations support the view that the immune system is far from
being infallible against pathogens.
3. Before modern medicine, people succumbed to infections at much earlier age not
living long enough to get cancer
The demographic transition from high to low mortality (36) occurred following the discovery of
antibiotics and successful immunization programs. Before these medical achievements the
likelihood of an individual dying prematurely from infectious diseases was as high as 40%.
4
As Mukherjee emphasized, prior to the miracles of modern medicine, “people didn’t live long
enough to get cancer. Men and women were long consumed by tuberculosis, dropsy,
cholera, smallpox, leprosy, plague, or pneumonia (37).”
In contrast to the 40% death rate by infections, only one-third of humans are struck by
cancer, mainly with advancing age (38). Fortuitously, good supporting historical evidence is
available in the Statistical Yearbook of Hungary from 1896 about all-causes and cause-
specific mortality. We created an interactive figure using the visualization tool Krona (39).
5
6
The data show that deaths due to infections were 27%, whereas deaths due to cancer were
only 2%. It must be noted that the mortality rate of 27% from infectious diseases is a
conservative estimate, since pneumonia, bronchitis, meningitis and encephalitis were not
included therein in the infectious disease category. It is noteworthy that a similar difference
between the mortality rate from infectious disease and other disease states was recorded in
the USA. Cutler and Meara reported that at the beginning of the 20th century, death due to
infections was 32%, whereas only 5% due to cancer.
7
In the low-income countries, where
the miracles of modern medicine are still not readily available, this ratio (28% vs. 6%) had not
changed much by 2012.
8
9
10
4. Slow growing tumor cells induce tolerance
3
http://www.the-scientist.com//?articles.view/articleNo/42274/title/Wrangling-Retrotransposons/
4
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm#fig1
5
http://digitalia.lib.pte.hu/books/magyar-statisztikai-evkonyv/htm/1896/htm/094.htm
6
http://kerepesi.web.elte.hu/causes_of_death/1896_leading_causes_of_death_en.txt-krona.html
7
See Table 3 in http://www.nber.org/papers/w8556
8
http://apps.who.int/gho/data/view.main.CODWBINCLOINCV?lang=en
9
http://kerepesi.web.elte.hu/causes_of_death/low_income_leading_causes_of_death.txt-Krona.html
10
http://kerepesi.web.elte.hu/causes_of_death/high_income_leading_causes_of_death.txt-Krona.html
Bakacs et al. Viruses as nature’s genetic engineering tools January 11th 2016
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Carcinogenesis is a long-lasting step-by-step progression of early-stage lesions of cancer
into frankly malignant cells. In addition, it is noteworthy that it takes as long as 12 years for
cancer cells to reach a population size of 109 cells contained within ~0.5cm3, weighing ~0.5g
(40). Consistent with this, the average age of women with pre-invasive lesions was about 20
years lower than for those with invasive lesions.
11
The risk of cancer increases exponentially
with age (41). The risk of breast cancer, for example, increases from 1 in 400 at thirty years
of age to 1 in 9 at seventy years of age. Age-incidence curves rise sharply above the age of
50 years and are informative about the dynamics of tumor progression, the straight line
showing a fit with power 4.8 (42).
The slow growth of tumor cells is consistent with Pardoll’s suggestion that specific
immune surveillance systems operate at early stages of tumorigenesis, whereas established
tumors induce immune tolerance (43). The latter phenomenon is explained by the
discontinuity theory of immunity claiming that the speed of antigenic change determines T
cell activation. That is, the elimination of target cells is induced by an antigenic discontinuity,
following a sudden modification of molecular motifs with which T cells interact (44).
The paradox of cancer appears not to be “why does it occur”, but rather “why does it
occur so infrequently” (45). It perhaps bears repeating that in fact, most human malignant
tumors are latent for many years and became ‘old’ by the time they are detectable clinically,
when termed incipient cancer. Although two out of three humans never develop clinically
detectable cancer (38), most individuals with no apparent pathology, but having died of
trauma, at autopsies were discovered to have been harboring unsuspected microscopic
primary cancers (46) (47). The risk of suffering any cancer before the age of 40 is ~2%, but
by age 80 this risk increases to 50% (48). For this so called tumor dormancy, it was
suggested that cancer may be thought of as a chronic disease, which is kept in check by the
patients’ own immune system and physiological mechanisms (49).
5. The explosive replication speed of microbes can only be controlled with non-
cytopathic mechanisms
Bacteria double in 20 min, whereas viruses produce more than 1,000 progeny in a few hours
generating hundred-times more virus infected cells within a few days than cancer cells
develop during twelve years (see below). The question arises as to how do specific cytotoxic
T lymphocytes (CTL) cope with virus infected cells?
In this connexion hepatitis B and C virus (HBV, HCV) infections are good examples.
According to Guidotti and Chisari (50), in the unlikely event of all the 108 HBV-specific CTL in
the entire body entering the liver at the same time and all the 1011 hepatocytes quite
11
Siddhartha Mukherjee: The Emperor of All Maladies, p.290
Bakacs et al. Viruses as nature’s genetic engineering tools January 11th 2016
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commonly infected, for every 1,000 infected hepatocytes, there would be only one specific
CTL in the liver to cope with the infection. Obviously, 1:1000 ratio would be totally inadequate
for cytotoxic mechanism alone. Nevertheless, the immune system of most infected patients
clears the virus within a few weeks without serious liver disease. This fact indicates the
contribution of non-cytopathic mechanisms. Similarly, this occurs in HCV infections as well
(51).
6. The fallacy of the infectious disease vaccination model of cancer immune therapy
One of the greatest triumphs of medicine was the discovery of immunization against
infectious diseases. Successful vaccination programs have been developed against 27
different diseases. Vaccination against smallpox, which killed 300 to 500 million people even
in the 20th century, enabled the infection to be declared eradicated from the world in 1980.
12
Arising from the successes of vaccines against xenogeneic infectious diseases, the
tacit assumption historically has been that host immunity should be protective against
isogeneic cancer as well. Following the simple principle of logic, assuming that immunity
should be successful to defeat cancer as well, we submit that this makes it a fallacy. It is
useful to consider the following reasons: (i) most spontaneous tumors in humans have no
neoantigen (they are part of self), (ii) each tumor is a unique entity a unique invention of
nature (52), (iii) consistent with this, nearly all neoantigens in ipilimumab treated melanoma
patients were patient-specific and most likely represent “passenger” mutations that do not
directly contribute to tumorigenesis (53), but may have enhanced ipilimumab induced GVHD
and (iv) tumors grow very slowly compared to pathogens (even a fast growing tumor with a
doubling time of 10 days, less than 10 tumor cells will be present in a month, whereas 1011
hepatocytes are infected during the same time; see above). Due to these characteristics
human tumors either are unable to activate a sufficient number of antigen presenting cells
(APCs) or APCs are less efficient in responding to isogeneic variants to promote interleukin-2
(IL-2)dependent co-stimulation of T cell before tolerance will have generated (43).
Cancer immunotherapy trials conducted with the best available science resulted in
anecdotal responses such that the field of cancer immunotherapy did not quite succeed
fulfilling the great hopes of conquering cancer and began to lose credibility (54). Studies
initiated by James P. Allison led to the breakthrough via the immune checkpoint blockade.
That is a good example for the role of enhanced co-stimulation. Even innocuous substances
are able to induce immunization with ongoing co-stimulation as demonstrated by the rise in
the prevalence of allergic diseases that has continued in the industrialized world for more
12
https://www.gov.uk/government/publications/immunity-and-how-vaccines-work-the-green-book-chapter-1
Bakacs et al. Viruses as nature’s genetic engineering tools January 11th 2016
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than 50 years. Sensitization rates to one or more common allergens among school children
are currently approaching 40% to 50%.
13
These examples are persuasive enough to consider a critical re-examination of the
conventional two-signal theory invoking an obligatory co-stimulus for T cell activation as
described below.
7. The law of independent T cell activation is consistent with recent clinical observations
The consensus view still is that the immune system is a complex and powerful defense
mechanism (55). In order to keep this power under control T cell antigen receptor (TCR)
input must be complemented by CD28 co-stimulation to promote interleukin-2 (IL-2)
dependent proliferation, as described by the classic “two-signal” model of T cell activation
(56). This is taken to mean that each cell requires the conjoint signals within it for these two
receptors triggering activation to a state suitable for cell division (57).
In contrast, the law of independence of T cell activation described by Gett and Hodgkin
(58) states that the internal mechanisms that control the rate of division, the likelihood of
surviving and the likelihood of undergoing a differentiation operate independently within a
cell. In fact, the strength of a T cell response can be predicted by adding together the
underlying signal components from the TCR, co-stimulatory receptors, and cytokines. This
law resolved the co-stimulation paradox and provided a quantitative paradigm for
therapeutically manipulating immune response strength (59). Consequently, there is no need
for an obligatory co-stimulus for the decisions between tolerance and activation.
This law is confirmed by recent clinical observations, which demonstrated that one
signal alone was sufficient to trigger uncontrolled T cell stimulation via the CD28 receptor or
the CTLA-4 receptor (17). The cytokine storm induced by the “superagonist” anti-CD28 mab
(TGN1412) in the Northwick Park, Harrow, clinical trial catastrophe demonstrated that T
cells, depending on the high ligand concentration (see in (60) especially fig. 2), can be
activated via a single receptor. Similarly, anti-CTLA-4 antibodies (during ipilimumab therapy)
were able to stimulate the T cell system indirectly by blocking the CD28 antagonist CTLA-4
co-receptors. In these interactions T cell pathways responsible for immune down-regulation
were interrupted resulting in a dose-dependent, unrestrained, pan-lymphocytic T cell
activation. This then turned homeostasis into overt autoimmunity (61) (62), thereby provoking
an autologous graft versus host-like disease (GVHD) with severe, life-threatening
autoimmune side effects.
The one-signal model a painting with broad brush strokes
13
World Health Organization. White Book on Allergy 2011-2012 Executive Summary. By Prof. Ruby Pawankar,
MD, PhD, Prof. Giorgio Walkter Canonica, MD, Prof. Stephen T. Holgate, BSc, MD, DSc, FMed Sci and Prof.
Richard F. Lockey, MD.
Bakacs et al. Viruses as nature’s genetic engineering tools January 11th 2016
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Numerous receptor-mediated signals are delivered to T cells, governing their survival,
differentiation and proliferation. For the sake of simplicity, only two positive and one negative
signals are depicted in Figure 1.
In our model stochastic processes govern all the events. Based on the law of
independent T cell activation (58), the likelihood of survival, activation, undergoing a
differentiation change and clonal division operate independently within a cell. In other words,
one signal should be sufficient to instigate these events. Signal strength (via one or several
receptors) determines the outcome of T cell activation. Low affinity, short-lasting TCR ligation
ensures T cell survival, increased ligation time and or affinity induces cytotoxicity, whereas
the strongest signal (long ligation time and or high affinity) induce clonal division. This may
require stimulation via more than one receptor (e.g. TCR and CD28) such that the TCR-
dependent effects are strengthened by co-stimulation amplifying the T cell number
exponentially through minimal kinetic alterations. The activities of the model are described in
greater detail hereunder the following headings: (1) T cell survival (2) tumor prevention; (3)
defense against primary infections; (4) secondary immune response; (5) autoimmune
disease and (6) iatrogenic tolerance breakdown.
1. T cell survival
As already stated, the homeostatic coupled system functions via an internal dialogue
between positively selected low affinity complementary T cells and host cells (10) (11).
Recognition of ubiquitous and constitutive self-antigens by complementary T cells not only
reliably sustains natural tolerance preventing dedifferentiation, but also ensures attacking
cells presenting non-self peptides (see below).
2. Tumor prevention (surveillance)
The success of multicellularity depends upon the evolution of mechanisms that are able to
suppress the ability of virtually every cell in an organism with the information and the
potential to propagate rapidly (48). Rinkevich suggested that the immune system has
developed as a surveillance machinery for nascent selfish cells stemming from a kin
organism or from transformed cells within the organism of origin (3). Protective mechanisms
that evolved over millions of years are indeed capable to keep the incidence of cancer very
low (~2%) during reproductive age (48). It should, however, be noted that despite
appearances, the mechanism of primary protection against cancer is different from primary
protection against infections (see below).
We hypothesize that cancer protection is carried out via cognate (complementary)
TCR-MHC interactions (see Fig. 1) such that T cells keep the number of somatic cells
constant. Paraphrasing George Klein (38), it would appear that evolution may have exploited
Bakacs et al. Viruses as nature’s genetic engineering tools January 11th 2016
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over expression of a relatively limited number of common resistance genes to nip in the bud
the incipient cancerous foci. Such preventive protection is all the more important since
cancer is a state in which the epigenome is allowed to have greater plasticity than it is
supposed to have in normal somatic tissues. It was argued that this increased epigenetic
plasticity allows for selection in response to the cellular environment for cellular growth
advantage at the expense of the host (63).
Up-regulated genes in transformed cells increase the expression of self peptides,
which in turn, increase their affinity for interaction with the TCRs. This way, short-lasting life-
sustaining physiological stimulation of T cells is extended into a longer-lasting one that
induces cytotoxicity. This local destructive autoimmunity eliminates altered (pre-cancerous)
host cells. This is encompassed in the real meaning that molecular complementarity between
TCR and MHC molecules puts strict limits on variations. The proof-of-principle that amplified
or overexpressed genes are capable of inducing robust antitumor efficacy in T cells without
destruction of normal tissues was recently demonstrated (64).
Notwithstanding, cancer is virtually inevitable in complex, long-lived, multicellular
organisms. Extrapolating from the risk of affliction with any cancer, practically everybody will
have developed cancer as human lifetime approaches one-hundred years (see figure 4 in
(48)). This is due to the fact that somatic mutations inevitably accumulate with time and
capable to overcome the suppressive mechanisms.
3. Defense against primary infections
The probability is greater that the presentation of foreign peptides decreases rather than
increasing the affinity for interaction with the TCRs during primary infections (10). While
specific TCR-MHC contacts are inhibited, CD80/86-CD28 engagements are not. Microbial
products (e.g. endotoxin) increase the local concentration of the CD80 and CD86 ligands on
APCs (e.g. dendritic cells) by stimulating toll like receptors (TLRs). CD28 receptors of
bystander T helper cells (Th) will then be saturated with CD80/86 ligands. Consequently, Th
cells in the anatomical region are activated via the CD28 receptor alone (60). This triggers a
limited beneficial local cytokine storm unleashing polyclonal T cytotoxic (Tc) cell proliferation
to attack infected cells. These events initiate predominately immunopathology and to a lesser
extent, autoimmunity by inducing indiscriminately anti-self and anti-non-self killing. This may
well be thought of as a physiological local transplantation reaction.
4. Pathogen specific secondary immune response
In the presence of ongoing robust non-associative CD80/86-CD28 interactions (co-
stimulation), there is always a possibility that rare T cell (and B cell) clones with higher affinity
may well recognize foreign peptides (antigens) via MHC-Ag-peptide-TCR signal (or via
Bakacs et al. Viruses as nature’s genetic engineering tools January 11th 2016
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BCR), particularly when a significant fraction of host cells is infected and viral load is high (for
example in hepatitis, see in (51)). Such higher affinity specific interactions would then drive
activation, proliferation of T cell clones, and eventually lysis of infected cells, as described by
the conventional two-signal models. Having cleared the infection, specific T cells would
expand into memory type T cell clone, while B cells would differentiate into antibody
producing plasma cells (65). Specific T and B cell activation, proliferation and lysis of infected
cells, therefore, obey the rules of the conventional two-signal model.
5. Accidental autoimmune disease
During an infection, when infected host cells lose their complementary Tc cell contact,
autoreactive Tc cells with high affinity for a self peptide-MHC complex may be generated
randomly, albeit with a small probability. This is consistent with the observations that
autoimmunity might be thought of as a by-product of the immune response to microbial
infection (66).
6. Ipilimumab therapy and unanticipated consequences of iatrogenic breakdown of
tolerance
Ipilimumab therapy that induces blockade of CTLA-4 disabling the brakes on T cells,
artificially prolongs the survival signal of complementary (autoreactive) T cells and turns
homeostasis into overt autoimmunity. This induces a dose-dependent, unrestrained, pan-
lymphocytic T cell activation, which lasts so long as the CTLA-4 receptor blockade is
sustained. This unfortunately results in unintended severe widespread, often life-threatening
autoimmune side effects, including autologous graft versus host disease (GVHD). Under
such conditions a genuine monoclonal autoimmunity may also be triggered (17) (18) (19).
Acknowledgements
The authors thank Professor Alfred I. Tauber, Chairman of the Board of Governors,
University of Haifa, Israel and Baruch Rinkevich, senior scientist, Israel Oceanographic and
Limnological Research (IOLR), Haifa, Israel for their critical reading, comments and
suggestions for the MS.
Conflict of interest
T.B. has a pending patent application and he is the CSO of Pret Therapeutics Inc.
Bakacs et al. Viruses as nature’s genetic engineering tools January 11th 2016
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Figure:
Figure 1: Activation of T-cells
Fig.1. Numerous receptor-mediated signals are delivered to T cells, which direct their
survival, activation, differentiation and proliferation. For the sake of simplicity, here only an
APC and a T cell are depicted with two ligands on APC (MHC and B7 [CD80/CD86]) and
three receptors on T cell (TCR; CD28; and CTLA-4). The TCR and the CD28 receptor
mediated signals are stimulatory, whereas the CTLA-4 receptor mediated signal is inhibitory
in our model. Further details see in the text.
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