1

CHAPTER I
INTRODUCTION

1.1

Background
Cancer is a group of diseases characterized by unregulated cell growth and spread
of abnormal cells. Unregulated cell growth without invasion is a feature of benign
neoplasms, or new growths. However, cancer is a synonym for malignant
neoplasm. In addition, the terms of cancer can be divided into 2 by its location
such as in epithelial tissues are called carcinomas; cancers of nonepithelial
(mesenchymal) tissues are called sarcomas. The aetiology of cancer is usually
caused by both external factors (tobacco, chemicals, radiation, and infectious
organisms) and internal factors (inherited mutations, hormones, immune
conditions, and mutations that occur from metabolism). These causal factors may
act together or in sequence to initiate or promote carcinogenesis and the
development of most cancers requires multiple steps that occur over many years.
The accumulation of genetic lesions may lead through an identifiable progression
of altered phenotypes such as hyperplasia, adenoma, dysplasia, carcinoma in situ,
and invasive/metastasis carcinoma respectively. When countries are grouped
according to economic development, cancer is the leading cause of death in
developed countries and the second leading cause of death in developing countries
(following heart diseases). According to estimates from the International Agency
for Research on Cancer (IARC), there were 12.7 million new cancer cases in 2008
worldwide, of which 5.6 million occurred in economically developed countries
and 7.1 million in economically developing countries. By 2030, the global burden
is expected to grow to 21.4 million new cancer cases and 13.2 million cancer
deaths simply due to the growth and aging of the population, as well as reductions
in childhood mortality and deaths from infectious diseases in developing
countries.1
Nowadays beside external and internal factors which can induce carcinogenesis,
many researches have shown that cancer has strong correlation with the immune
system.2 Immune system have a pivotal role for carcinogenesis because it can
directly or indirectly induce inflammation where the main reason as a defences

mechanism but from the literature it can caused carcinogenesis by loss of tissue
architecture due to tissue destruction, excessive tissue remodelling, protein and
DNA alterations due to oxidative stress, and other circumstances. But the term of
inflammation which can make carcinogenesis is not for acute inflammation,
especially just for the chronic inflammation. Chronic inflammation make
interactions between innate and adaptive immune cells are disturbed. Then it
makes either innate or adaptive immune system will modulate cancer via direct or
direct mechanism.3 Through direct mechanism, either innate or adaptive cell
immune system, will induce DNA damage by the generation of free radicals and
paracrine regulation of intracellular pathways (through nuclear factor B).
Whereas through indirect mechanism, either innate or adaptive cell immune
system, will induce promotion of angiogenesis and tissue remodelling by the
production

of

growth

factors,

cytokines,

chemokines

and

matrix

metalloproteinases, promotion of tumour development by humoral immune

responses that increase chronic inflammation in the tumour microenvironment,
promotion of tumour growth by regulatory T cells that suppress antitumour T-cell
responses, and suppression of antitumor adaptive immune responses .3 All of them
indicate that immune system have a critical role for carcinogenesis.
In addition immune system have a role for carcinogenesis, immune system is
responsible as an immunesurveilance against cancer too. Interest in cancer
immunology stemmed from Paul Ehrlich in the late 1800s when he used
antibodies targeting both microbes and tumours. He thought that tumour have an
antigenic profile distinct from normal cellular counterparts. And after that Phren
did extensive study on the phenomenon of tumour rejection in immunocompetent
patients.4 The successful of their experiments are because cancer cells have a
distinct antigen in its intracellular protein either because of altered genetic or
epigenetic features which called neoantigen. It is called altered genetic because
there is additional, deletions, amplifications, or chromosomal rearrangement
which result in new genetic sequences and produce distinct intracellular protein,
tumour-specific antigen, where it cannot recognized as a self-antigen. Another is
called epigenetic feature because there is global alterations in DNA methylation as
well as chromatin structure in tumour cells results in dramatic shifts in gene

expression. DNA methylation causes genes will turn on that are normally silent
and become overexpressed than normal cell.5 All of them make tumour or cancer
susceptible against immune system especially innate immune system.
Even though the immune system will eliminate distinct cell such as tumour,
developing tumour have adaptation mechanism in a manner that either turns off
potentially harmful to the tumour by immune response or creates a local
microenvironment inhibitory to the tumouricidal activity of immune cells. These
processes called immunotolerance and immunoevasion have become a central
focus of cancer immunology efforts.
This topic about cancer immunology is very interesting because immune system
have many complex mechanisms for cancer in human body. In one side chronic
inflammation due to immune system is one of the main factors for carcinogenesis.
In addition paradoxically immune system have a special ability to differentiate
self-antigen than non-self antigen which make it can recognize cancer cells and
induce them to be eliminated by its mechanism. And another is cancer cells can
adapt to their environment and make them silent by targeting of immune system.
So that is why the science of cancer immunology has emerged to understand this
from the basic concept of immune system, mechanisms of immune system
responsible for carcinogenesis, immune system as an immune surveillance against
cancer, and mechanism of cancer tolerance from the immune system. We will
discuss it further in the next chapter
1.2

PROBLEM IDENTIFICATION
Based on the background above so we can make several problem identifications:
1.
2.
3.
4.

1.3

What is the basic concept of immune system?

How mechanisms of immune system responsible for carcinogenesis?
How mechanisms of immune system as a immune surveillance against cancer?
How mechanisms of cancer tolerance from the immune system?

AIMS

There are several aims for this literature review:

1. To know the basic concept of immune system
2. To know the mechanisms of immune system responsible for carcinogenesis
3. To know the mechanisms of immune system as an immune surveillance
against cancer
4. To know the mechanisms of cancer tolerance from the immune system
1.4

BENEFITS
Hopefully this literature review able to give several benefits such as:
1. To enrich our knowledge to the understanding of cancer immunology from the
concept of immune system, immune system induce carcinogenesis,
immunesurveillance against cancer, until immunetolerance against immune
system.
2. To give feedback either to the academician or public about issues in health
especially in cancer.

CHAPTER II
LITERATURE REVIEW

2.1

The Basic Concept of Immune System

Immunity is divided into two parts determined by the speed and specificity of the
reaction. These are named the innate and the adaptive responses, although in
practice there is much interaction between them. The term innate immunity is
sometimes used to include physical, chemical, and microbiological barriers, but
more usually encompasses the elements of the immune system (neutrophils,
monocytes, macrophages, complement, cytokines, and acute phase proteins)
which provide immediate host defence. The highly conserved nature of the
response, which is seen in even the simplest animals, confirms its importance in
survival.6 Adaptive immunity is the hallmark of the immune system of higher
animals. This response consists of antigen-specific reactions through T
lymphocytes and B lymphocytes. Whereas the innate response is rapid but
sometimes damages normal tissues through lack of specificity, the adaptive
response is precise, but takes several days or weeks to develop. The adaptive
response has memory, so that subsequent exposure leads to a more vigorous and
rapid response, but this is not immediate.7 Now we will discuss it further either
innate or adaptive immune system respectively.

2.1.1 The Components of Innate Immune System

The innate immune system consists of all the immune defences that lack
immunologic memory. Thus, a characteristic of innate responses is that they
remain unchanged however often the antigen is encountered. The cellular
components of innate immunity consist of:
a. Macrophage: Macrophages (derived from blood-borne monocytes) possess
receptors for carbohydrates that are not normally exposed on the cells of
vertebrates, such as mannose, and therefore can macrophage can differentiate
between non-self and self-molecules. In addition, macrophages have receptors
for antibodies and complement, so that the coating of microorganisms with
antibodies, complement, or both enhances phagocytosis. Phagocytosis means
that macrophages have ability to engulfed microorganism where it will be
exposed to a wide range of toxic intracellular molecules, including superoxide

anion, hydroxyl radicals, hypochlorous acid, nitric oxide, antimicrobial cationic

proteins and peptides, and lysozyme. After that, the hydrolysed fragments will
be presented on the surface of macrophages by Major Histocompatibility-Class
II (MHC-II) where it specialize interact and activate T-Helper (CD4) cells. In
addition, macrophages have MHC-I too which are specialized for presented
epitopes of antigen, caused by virus infection particularly, to the Cytotoxic TCells (CTL) which express the CD8 molecule.6
b. Neutrophil: Neutrophils, like most cells involved in immune responses, are
not static within a particular compartment, but are mobile cells that travel
round the body. They normally flow freely in the blood as the circulating pool,
or roll along the vascular endothelium as the marginating pool. To home to a
site of infection, neutrophils use a multistep process involving proinflammatory
mediators, adhesion molecules, chemoattractants, and chemokines. Neutrophils
are the earliest activated innate immunity when there is infection or tissue
damage. As same as macrophages, it uses phagocytosis mechanisms to
eradicate infection or debris of tissue. In their neutrophil cytoplasm granules
there is highly toxic cationic proteins and enzymes (e.g., myeloperoxidase and
lyzozyme) which functions are to killing pathogenic microorganism inside
them. And neutrophil will be more effective 100-fold if the particle is first
opsonised with specific antibody or complement (C).8
c. Natural Killer Cells: Natural killer cells have the morphology of lymphocytes
but do not bear a specific antigen receptor. They recognise abnormal cells in
two ways. First, they bear immunoglobulin receptors (FcR) and bind antibodycoated targets leading to antibody-dependent cellular cytotoxicity. Second, they
have receptors on their surface for MHC class I. If on interaction with a cell,
this receptor is not bound, the natural killer cell is programmed to lyse the
target. This is achieved by secretion of perforins onto the surface of the cell to
which the natural killer cell has adhered. Perforins make holes in the cell
membrane and granzymes are injected through the pores. The granzymes cause
induction of apoptosis in the target. Normal host cells are MHC class I
positive, the binding of this molecule to its receptor on the natural killer cell
inhibits the death pathway. Cells infected by virus or there is a malignant
transformation usually lack of MHC class I molecules, it means that there is

no inhibitory signal from the killer-inhibitory receptor, and the natural killer
cell kills the abnormal target cell Although this may offer some advantage to
the pathogen impairing recognition by cytotoxic T cells, it does leave them
open to natural killer cell attack.6,8
d. Mast Cells and Basophil: Basophils and mast cells have similar functional
Characteristics. Both type of cells have high-affinity receptors for IgE FcRI
(CD23) which rapidly absorb any local IgE. Crosslinking of these receptors by
the binding of antigen to IgE leads to degranulation and release of preformed
mediators, such as the vasoactive amines, histamine and serotonin. These
mediators are responsible for allergic reaction such as eczema, hay fever, and
asthma.6,8
e. Eosinophils: The main physiological role of eosinophils is in protection of the
host from parasitic (particularly nematode) infections. Such infections induce
antigen-specific IgE production, the antibodies coating the organism.
Eosinophils bind to the antibody using their low affinity receptors (FcRII).
Unlike macrophages and neutrophils, eosinophils are only weakly phagocytic
and, on activation, probably kill parasites mainly by releasing highly cytotoxic
mediator such as cationic proteins and reactive oxygen metabolites from its
f.

large granules into the extracellular fluid.6,8

Complement: The complement system has several important functions in
innate immunity and consists of at least 20 serum glycoproteins, some being
regulatory. These are activated in a cascade sequence, with amplification
stages. This means that activation of a single molecule will lead to thousands of
molecules being generated. There are three pathways and all of them activate
the central C3 components which lead to the assembly of C5-C9 forming a
transmembrane pore (membrane attact complex) in the cell surface. It caused
cells become osmotic and lead to lysis. In addition to lysis of organisms,
complement has other anti-infective functions. There is the opsonic action of
C3b, the release of soluble C3a and C5a, which are anaphylatoxins and
increase vascular permeability allowing proteins, such as antibody, to penetrate
the tissue, and the chemotactic activity of C5a that induces an inflammatory
infiltrate. Complement also has a role within the specific immune response; its
activation and deposition within immune complexes helps to target these to

complement-receptor bearing antigen-presenting cells, such as B lymphocytes

and follicular dendritic cells.8

Picture 1. Three pathways of complement induce cell lysis

2.1.2 The Components of Adaptive Immune System
The characteristic of adaptive immunity is the use of antigen-specific receptors on
T and B cells to drive targeted effector responses. The cellular components of
adaptive immune system consist of:
a. T-Helper (CD4) Cells: CD4 T cells can be divided into two major types. Type
1 (Th1) helper T cells secrete interleukin- 2 and interferon- but not
interleukin-4, 5, or 6. Interleukin 2 stimulates CD8+ T cell division and
cytotoxicity, by decreasing activation thresholds and interferon- activates
macrophages to kill intracellular pathogens such as mycobacteria, fungi, and
protozoa and induces natural killer cells to cytotoxicity. On the other hand Type
2 (Th2) helper T cells secrete interleukin-4, 5, 6, and 10 but not interleukin-2 or
interferon-. Interleukin 4 induces class-switching in B cells to IgE production
and interleukin 5 promotes the growth of eosinophils. Interleukin 4 provides
positive feedback to induce further Th 2 responses and suppress Th 1
differentiation. Thus the Th 2 response is associated with allergic disease.7
b. T-Cytotoxic (CD8) Cells: CD8 T Cells have special function to elimination of
virally infected cells which provide the control of intracellular infections that
cannot be achieved by the innate system. The infected cell marks itself as a
target for the cytotoxic T cell by displaying peptides derived from intracellular
viral protein on its surface. These viral peptides are bound to the peptidebinding regions of class I MHC molecules. After binding to the MHC-I, CD8 T
Cells kill the infected cell by two different mechanisms. First, they can insert

perforins into the cell membrane, in the same way as natural killer cells.
Cytoplasmic granules containing granzymes pass through the pores from the T
cell into the target cytoplasm. These activate caspase enzymes that induce
DNA fragmentation and cell apoptosis. Second, they can bind to the target cell
surface Fas (death inducing) molecules by their Fas ligand (FasL), which also
activates apoptosis.7,8
c. B-Cells: B cells produce antibody. This serves to neutralise toxins, prevents
organisms adhering to mucosal surfaces, activates complement, opsonises
bacteria for phagocytosis, and sensitises tumour and infected cells for
antibodydependent cytotoxic attack by killer cells. Thus antibody acts to
enhance elements of the innate system. Different classes of antibody
predominate at different compartments of the body (IgM being intravascular,
IgG the main antibody of the blood and tissues, IgA in secretions). Most B cells
remain in the lymphoid tissue, the recirculating pool being small. B cells
usually recognise free antigen brought to lymphoid tissues. During subsequent
infections by the same pathogen B cells can be activated by follicular dendritic
cells which bear Fc and complement receptors, bind immune complexes
containing antigen, and trap this to activate the B-cell response (follicular
dendritic cells are a different family to dendritic cells and do not endocytose
and present antigen).7

Picture 2. Role of B-cell and T-cell as an adaptive immune system

10

2.2

Mechanisms of Immune System Responsible for Carcinogenesis

The mechanisms of immune system to induce carcinogenesis process is not in
directly manner, but especially because of inflammation as another effect by
immune system. But not all inflammation is risk to cancer formation and
progression, just in chronic inflammation condition. This hypothesis arise that
many malignancies come from infection and inflammation. there is a growing
body of evidence that many malignancies are initiated by infections upwards of
15% of malignancies worldwide can be attributed to infections, a global total of
1.2 million cases per year.2 If it is not clear immediately, persistent infections
within the host induce chronic inflammation. Chronic inflammation leads
Leukocytes and other phagocytic cells induce DNA damage in proliferating cells,
through their generation of reactive oxygen and nitrogen species that are produced
normally by these cells to fight infection which have been previously describe. 6,7,8
These species react to form peroxynitrite, a mutagenic agent. All of them resulting
in permanent genomic alterations such as point mutations, deletions, or
rearrangements. Indeed, p53 mutations are seen at frequencies similar to those in
tumours in chronic inflammatory diseases such as rheumatoid arthritis and
inflammatory bowel disease.
There are some examples of infection either by bacteria or virus can induce
chronic inflammation which lead to carcinogenesis. First, there is strong
association of chronic inflammation with malignant diseases is in colon
carcinogenesis arising in individuals with inflammatory bowel diseases, for
example, chronic ulcerative colitis and Crohns disease. Second, Hepatitis C
infection in the liver predisposes to liver carcinoma, an increased risk of bladder
and colon carcinoma is associated with schistosomiasis. Third, Helicobacter
pylori infection is the worlds leading cause of stomach cancer and this gramnegative bacterium H. pylori is established as a definite carcinogen for the
development of gastric cancer the second most common type of cancer
globally.9 Fourth, Infectious viral agents, for example, DNA tumour viruses, may
also directly transform cells by inserting active oncogenes into the host genome,
although other mechanisms also are responsible, such as human papilloma virus,
hepatitis B virus (HBV) or Epstein-Barr virus.10

11

2.3

Mechanisms of Immune System as An Immune Surveillance Against Cancer

The immune system has three primary roles in the prevention of tumors. First, the
immune system can protect the host from virus-induced tumors (e.g: HBV/HCV,
HPV, etc) by eliminating or suppressing viral infections. Second, elimination of
pathogens and prompt resolution of inflammation can prevent the establishment of
an inflammatory environment conducive to carcinogenesis. Third, the immune
system can specifically identify and eliminate tumor cells on the basis of their
expression of tumor-specific antigens or molecules induced by cellular stress. The
third process is referred to as tumor immune surveillance, whereby the immune
system identifies cancerous and/or precancerous cells and eliminates them before
they can cause harm.
The fundamental hypothesis of immunosurveillance have begun nearly a halfcentury ago. Lewis Thomas proposed that a natural role for the immune system
was to survey the body for tumors similarly to the way the immune system
surveys the body for invading foreign pathogens. He said that tumors were
proposed to be distinguished from self tissues due to its expression of tumor
specific antigens (TSAs). And his hypothesis have become a new understanding
how immune system protect the body against cancer by immunosurveillance.
Because the immune system exerts both host-protecting and tumorsculpting
effects on developing tumors, the term cancer immunosurveillance may no longer
be appropriate to describe the process accurately because, in its original form, it
was thought to function only to protect the host and to act only at the earliest
stages of cellular transformation. That is why the term of immunoediting arise to
describe more appropriately the dual host-protecting and tumor-sculpting actions
of the immune system that not only prevent but also shape neoplastic disease
Immunoediting means a process by which a person is protected from cancer
growth and the development of tumour immunogenicity by their immune system.
It has three main phases: elimination, equilibrium and escape.11 These three phases
is called three Es that will be discussed further:
a. Elimination Phase: The elimination phase of cancer immunoediting is exactly
the same process described in the initial theory of tumor immune surveillance,

12

whereby the immune system detects and eliminates tumor cells that have
developed as a result of failed intrinsic tumor suppressor mechanisms. The
elimination phase can be complete, when all tumor cells are cleared, or
incomplete, when only a portion of tumor cells are eliminated. The complete
elimination phase consists of the following four phases:
- Phase 1: The first phase of elimination involves the initiation of
antitumor immune response. Cells of the innate immune system
recognize the presence of a growing tumor which has undergone
stromal remodeling, causing local tissue damage. This is followed
by the induction of inflammatory signals which is essential for
recruiting cells of the innate immune system (e.g. natural killer
cells, natural killer T cells, macrophages and dendritic cells) to the
tumor site. During this phase, the infiltrating lymphocytes such as
the natural killer cells and natural killer T cells are stimulated to
-

produce IFN-gamma.11
Phase 2:
In the second phase of elimination, newly
synthesized IFN-gamma induces tumor death (to a limited
amount) as well as promoting the production of chemokines
CXCL10, CXCL9 and CXCL11. These chemokines play an
important role in promoting tumor death by blocking the
formation of new blood vessels. Tumor cell debris produced as a
result of tumor death is then ingested by dendritic cells, followed
by the migration of these dendritic cells to the draining lymph
nodes. The recruitment of more immune cells also occurs and is
mediated by the chemokines produced during the inflammatory

process.11
Phase 3:

In the third phase, natural killer cells and

macrophages transactivate each others by the reciprocal

production of IFN- and IL-12. This promotes more killing of
cancer again by these cells via apoptosis and the production of
reactive oxygen and nitrogen intermediates. In the draining lymph
nodes, tumor-specific dendritic cells trigger the differentiation of

13

Th1 cells which in turn facilitates the development of CD8+ T

-

cells.11
Phase 4:

In the final phase of elimination, tumor-specific

CD4+ and CD8+ T cells home to the tumor site and the cytolytic
T lymphocytes then destroy the antigen-bearing tumor cells which
remain at the site.11
In the case of partial tumor elimination, tumor cell variants which have
survived the elimination phase will enter the equilibrium phase:
b. Equilibrium Phase: During this period tumor cells either remain dormant or
continue to evolve, accumulating further changes (such as DNA mutations or
changes in gene expression) that can modulate the tumor-specific antigens and
stress-induced antigens that they express.12 As this process continues, the
immune system exerts a selective pressure by eliminating susceptible tumor
clones where possible. Lymphocytes and IFN-gamma exert a selection pressure
on tumor cells which are genetically unstable and rapidly mutating. And if
tumor cell variants which have acquired resistance to elimination make them
enter the escape phase.13
c. Escape Process: in this phase, surviving tumor variants that have acquired
insensitivity to immunologic detection and/or elimination through genetic or
epigenetic changes begin to expand in an uncontrolled manner. This results in
clinically observable malignant disease that, if left unchecked, results in the
death of the host.12,13

14

Picture 1. Three phases mechanisms of immunoediting

2.4

Mechanisms of Cancer Tolerance And Evade From The Immune System

Immunologic tolerance to a particular set of antigens is the absence of an immune
response against those antigens, while normal responses to other antigens are
preserved. There are a number of mechanisms by which tumor may actively
evade, silence, suppress, or tolerance with immune system. A major factor
limiting immune recognition of cancer cells is the fact that tumor arise from the
organisms own tissue and therefore mainly express self antigen to which the
individuals T cells have been tolerized, either centrally or peripherally. Before we
learned further about immunotolerance in cancer, firstly we have to know the
basic principles of tolerance.

2.4.1 The Basic Principles of Tolerance

Tolerance to a given antigen can be achieved by either deletional mechanisms (ie,
elimination of the antigen-reactive cells) or by nondeletional mechanisms. The
term nondeletional refers to mechanisms in which antigen-specific cells are
unable to respond to the antigens their T-cell receptors (TCR) recognize. This can
be a result of either inadequate activation stimuli, leading to anergy, or active
suppression of the antigen-reactive T cell through regulatory cells. Deletional
tolerance to tumor antigens could not be broken via immunostimulation in the
tumor-bearing host because T cells with reactivity to these antigens would simply
be absent. Because most antigens expressed by tumors are, in fact, normal self
antigens to which deletional tolerance is likely to exist, the number of T-cell
clones in a given immune repertoire that can recognize tumors is likely to be

15

relatively small to begin with. Thus, it is easy to imagine that rapidly growing
tumors might out-run this immune response.
Another way of categorizing tolerance is based on the anatomic site and time in
development when T cells are tolerized. Thus, for thymus-dependent tolerance
induced during the maturation of a T cell, the term central tolerance has been
coined. Induction of tolerance extrathymically, after the mature T cell has exited
the thymus, is referred to as peripheral tolerance. Central tolerance is achieved
primarily through the process of negative selection. Developing thymocytes
undergo two selective processes based on the recognition of MHC/peptide
complexes by their uniquely rearranged TCRs. Positive selection refers to the
process in which thymocytes with a low affinity for a self MHC/peptide complex
expressed on epithelial cells of the thymic cortex are rescued from programmed
apoptosis by the signal provided by TCR ligation. The consequence of this
process is selection of a T-cell repertoire that preferentially recognizes host MHC
molecules complexed to peptides. These complexes in the periphery provide
signals to the T cells that optimize survival and readiness to respond to self MHCforeign peptide complexes for which they have higher affinity.14 Because it would
be undesirable to develop a mature T-cell repertoire that recognizes self
MHC/peptide complexes sufficiently well to be activated by them in the
peripheral tissues, thymocytes with high affinity for self MHC/peptide complexes
undergo a process of negative selection in the thymus, which leads to deletion via
apoptotic cell death. This occurs mainly at the CD4+CD8+ (double positive) stage
of thymocyte development, largely in the corticomedullary junction and medulla
of the thymus.15

16

Picture 2. Basic Concepts of Tolerance

Although antigen presented on a variety of cell types can lead to deletion, it
occurs most effectively as a consequence of the interaction of these immature
thymocytes with bone marrow-derived APC in the thymus, especially dendritic
cells (DC). In addition, other nondeletional mechanisms have been implicated in
the intrathymic tolerance of developing T cells. The overall consequence of these
processes is the emergence in the periphery of a T-cell repertoire that recognizes
self MHC/self peptide complexes preferentially but weakly and that includes cells
with potentially strong reactivity for self MHC/foreign peptide complexes.
Indeed, autoreactive T cells can clearly escape negative selection in the thymus,
and mechanisms exist that can tolerize these T cells once they mature and reach
the periphery. These mechanisms include anergy, deletion, and suppression. The
processes are incompletely understood and have been variously implicated in
tolerance induced under different circumstances.15 Some of these will be discussed
later in the context of tolerance to tumor or cancer antigens.
2.4.2 Mechanisms Immunotolerance of Tumor to The Immune System
Evidence from both murine immune systems as well as human tumors strongly
demostrates the capacity of tumors to induce tolerance to their antigen. This
capacity to induce immune tolerance may very well be the single most important
strategy that tumors use to protect themselves from elimination by the hosts
immune system. Tolerance to tumor seems to operate predominantly at the level
of T-Cells. B-cells tolerance to tumor is less certain, because there is little
evidence that the natural humoral response to tumors provides significant or
relevant antitumor immunity. To overcome this, there are several strategy of tumor
to escape from the immune system that we will learned it deeply:

17

a. Impaired Antigen Presentation: One strategy to escape from the adaptive

immune response is by impaired antigen presentation. In general, defects in
antigen presentation are more pronounced in metastatic lesions than in the
primary tumor. In some tumors, expression of the tumor antigen is downregulated, leading to enhanced tumor incidence and metastasis Moreover,
mutations of the antigen can result in escape from the initial response and
contribute to the heterogeneity of tumor lesions The heterogeneous expression
of multiple antigens may hinder the establishment of an efficient specific
immune response.16
In addition, another impaired antigen presentataion can be caused by a
reduction of MHC-I expression on the cell surface prevents recognition of
tumor cells by the immune system. Tumors frequently have a heterogeneous
pattern of MHC-I expression. Total loss of MHC-I is mainly caused by
mutations of the 2 microglobulin subunit, gene deletions or rearrangements,
point mutations, and defects in transcriptional regulation. These cause T-Cell as
an adaptive immune system cannot recognized them specifically.16 In other
pathways, tumor cells must prevent themselves against innate immunity such
as NK Cell because total MHC-I down-regulation may target the tumor for NK
cell attack. Therefore, the tumor needs further mechanisms to resist NK cellmediated lysis, such as the expression of MHC-I surrogates or analogues.16
b. Expression of Immunosuppresive Factors: Another strategy that tumors use
to

escape

from

immune-mediated

rejection

is

the

expression

of

immunosuppressive factors. These factors may be expressed by the malignant

cells themselves or by noncancerous cells present at the tumor site, such as
immune, epithelial, or stromal cells. The most prominent of these factors is
transforming growth factor (TGF-).17
TGF- is a cytokine that affects proliferation, activation, and differentiation of
cells of innate and adaptive immunity and thus inhibits the anti-tumor immune
response. Moreover, vascular endothelial growth factor (VEGF) is produced by
many tumor cells Besides its angiogenic properties, it inhibits the
differentiation of progenitors into dendritic cells. Further immunosuppressive

18

factors expressed by malignant cells are prostaglandins, interleukin (IL)-10,

macrophage-colony stimulating factor, and soluble tumor gangliosides which
all of them create a local microenvironment inhibitory to the tumoricidal
activity of immune cells.16
c. Direct Deletion: As previously describe about the basic concept of
immunotolerance, peripheral tolerance is used by cancer cell tolerance to
immune system. The peripheral tolerance to self antigen is established by
cancer cell by T cell deletion. As previously describe that repetitive stimulation
of T cells with the antigen will induces apoptosis, a process referred to as
activation-induced cell death (AICD). This process is mainly mediated via the
CD95/CD95L death system and costimulation via CD28 can rescue T cells
from AICD, implicating another important role for expression of B7 on tumor
cells.18 It has been recently demonstrated that expression by tumor cells of
human B7-H1, amember of the B7 family of costimulatory molecules, leads to
induction of T-cell apoptosis and might, thereby, contribute to immune escape
d.

of these tumors
Suppresion by Regulatory T-Cells: Another mechanism responsible for the
downregulation of T-cell responses against tumors might be the presence of
regulatory T cells within the tumor. CD4+, CD25+ regulatory T cells (Treg) have
been shown in mice to be crucially involved in the prevention of autoimmunity.
But recent studies indicate that present of Treg in the circumstances of cancer
can emerge tolerance of cancer by immune suppression. Mechanisms of
immune suppression by Treg vary and include production of inhibitory
cytokines such as IL-10 and TGF- which have discussed before will inhibit
proliferation, activation, and differentiation of cells of innate and adaptive
immunity.17 This kind of T-cells must be consider if there is a lot of T-cells in
cancer biopsy speciments, because it doesnt meaning a favourable outcome to
regress tumor but in contrary that is the sign of unfavourable outcome.

19

Picture 3. Immunetolerance mechanisms of cancer cell

CHAPTER III
CONCLUSION
Based on review of immunology in cancer that have been previously discussed, so
we can make several conclusion, they are:
1. Immunology in cancer is related with the basic of immune system. In basic
of immune system it can be divided into two general aspects, innate and
adaptive immune system. Cell components of innate immune system
consist of macrophage, neutrophil, natural killer (NK) cell, mast cell,
basophil, eosinophil and complement which act immediately non specific
when infection or tissue destruction occured. In addition, cell components
of adaptive immune system consist of T-Helper (CD4) cells which can be
divided into subspecialized T-Helper 1 and 2 (Th1 and Th2), Cytotoxic-T
Cells (CD8), and B-Cells that produce antibody where all of them act
specifically with antigen.
2. Immune system indirectly by its inflammation mechanisms can induce a
carcinogenesis process. It act especially in the chronic inflammation where

20

leukocytes and other phagocytic cells induce DNA damage in proliferating

cells, through their generation of reactive oxygen and nitrogen species
which induce form peroxynitrite, a mutagenic agent. All of them resulting
in permanent genomic alterations such as point mutations, deletions, or
rearrangements and result carcinogenesis process.
3. Immune system by its immunesurveillance mechanism will attact cancer.
The term of immunesurveillance changed with immunoediting where with
three Es will attact cancer cell, they are in elimination, equilibrium, and
escape phase respectively.
4. Tumor or cancer has several mechanisms for tolerance against immune
system. They are by impaired antigen presentation, express many
immunosuppresive factor to its environment milieu such as TGF-, VEGF,
prostaglandins, interleukin (IL)-10, macrophage-colony stimulating factor,
and soluble tumor gangliosides, then by direct deletion mechanism and the
suppression by regulatory T-cells.
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