Download Tumor immunology Dr Monem Alshok 20\12\2012 Tumor is

Tumor immunology
20\12\2012
Dr Monem Alshok
Tumor is Pathological cell masses derived by abnormal and uncontrollable clonal
expansion of single cell.Transformation of normal cells to malignant cells by:
a- Spontaneous mutation during daily cell division.
carcinogens,chemical carcinogens & viruses
b- It may be induced by : physical
Cells become antigenically different from normal cells&They are recognized and destroyed
by immune system.
Etiology Of Tumor :
1) Inherited : Expression of inherited oncogene e.g. viral gene incorporated into host gene
2) Viral:
- Human papilloma, herpes type 2, HBV, EBV (DNA)
- Human T-cell leuckemia virus (RNA)
3) Chemical:
- Poly cyclic hydrocarbons cause sarcomas
- Aromatic amines cause mammary carcinoma
- Alkyl nitroso amines cause hepatoma
4) Radiological: Ultraviolet & ionizing irradiation
5) Spontaneous: failure in the cellular growth control
Malignant Transformation is the proliferation of normal cells is carefully regulated.
However, such cells when exposed to chemical carcinogens, irradiation and certain viruses
may undergo mutations leading to their transformation into cells that are capable of
uncontrolled growth, producing a tumor or neoplasm. A tumor may be:
1) Benign, if it is not capable of indefinite growth and the host survives.
2) Malignant, if the tumor continues to grow indefinitely and spreads (metastasizes),
eventually killing the host. This uncontrolled growth may be due to upregulation of
oncogenes (cancer-inducing genes) and/or downregulation of tumor suppressor genes (that
normally inhibit tumor growth often by inducing cell death).
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Evidence for existence of an immune response against tumors:The following criteria serve
as evidence that tumors can elicit an immune response.
1. Tumors that have severe mononuclear cell infiltration have a better prognosis than those
that lack it.
2. Certain tumors regress spontaneously (e.g., melanomas, neuroblastomas).suggesting an
immunological response. Some tumor metastases regress after removal of primary tumor
which reduces the tumor load, thereby inducing the immune system to kill the residual
tumor..
3. Although chemotherapy leads to rejection of a large number of tumor cells, the few
tumor cells that evade the action of the drugs can outgrow and kill the host. However, the
immune system may be able to mount an attack against the few tumor cells that are spared
by the chemotherapeutic agent.
4. There is an increased incidence of malignancies in immunodeficient patients such as
AIDS patients who are susceptible to Kaposi sarcoma and transplant patients who are
susceptible to Epstein Barr virus (EBV)-induced lymphoma.
5. Tumor-specific antibodies and T lymphocytes (detected in cytotoxicity and proliferative
response assays) have been observed in patients with tumors.
6. The young and the old population have an increased incidence of tumors. These
members of the population often have an immune system that is compromised. Lastly
Hosts can be specifically immunized against various types of tumors demonstrating tumor
Ags can elicit an immune response
What is Oncogenes? Is a gene which, when mutated or introduced (by an oncogenic virus),
facilitates neoplastic proliferation.
In normal host the normal function of such genes is usually to produce factors involved in
growth control, the cell cycle or apoptosis.e call it (Proto oncogen )
Oncogenes can be broadly divided into two groups, according to whether their oncogenic
effect is gain of a pro-oncogenic gene (i.e. overactivity of a 'proto-oncogene' or gain of an
oncogenic virus) or loss of an endogenous anti-oncogenic 'tumour suppressor' function of
the proto oncogen .
What is the concept of immune surveillance?
Do tumour cells show differences from their normal cellular counterparts that the
immune system can recognize? If so, it would be interesting to know whether TAAs are
specific for the particular cancer involved or whether they represent simple differentiation
into malignant cells.If tumour associated antigens do exist, does the immune response
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directed against these antigens give rise to death of the tumour cell? During neoplastic
transformation, new antigen develop&The host recognize them as nonself antigens&Cell
mediated immune reactions attack these nonself tumor cells
* Immune response act as surveillance system to detect and eliminate newly arising
neoplastic cells.
This system include :
1) Natural killer (NK) cells They kill directly tumor cells,helped by interferon, IL-2
2) Cytotoxic T-cells They also kill directly tumor cells
3) Cell mediated T-cells (effector T-cells) They produce and release a variety of
lymphokines : a-Macrophage activation factor that activate macrophage
b-Gamma interferon and interleukin-2 that activate NK c-TNF (cachectine)
4) B-cells :Tumor associated antigens stimulate production of specific antibodies by host Bcells .These specific antibodies bind together on tumor cell surface leading to destruction of
tumor through:
a- Antibody mediated-cytotoxicity : kill IgG-coated tumor cells by Cytotoxic Tcells .
b- Activation of macrophages by release of Sensitized T-cells macrophage
activating factor causes activation of macrophages
c- IgG-coated tumor cells Activation of classical pathway of complement leading to
Lysis of tumor cells
Surface Antigens on Tumour Cells : Tumorigenesis may lead to expression of new antigens
or alteration in existing antigens that are found on normal cells. These antigens may
include membrane receptors, regulators of cell cycle and apoptosis, or molecules involved
in signal transduction pathways.
Tumour antigens fall into 2 broad categories:
1 .The tumour specific antigens (TSA) are unique, found only on tumour cells and are
eminently positioned as targets for immunologic attack.or called Tumor-specific
transplantation antigens (TSTA) which are unique to tumor cells and not expressed on
normal cells. These antigens may include membrane receptors, regulators of cell cycle and
apoptosis, or molecules involved in signal transduction pathways. They are responsible for
rejection of the tumor.
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2 . The tumour-associated antigens (TAA), by contrast, are found on tumour cells and some
normal cells as well.Also we call it Tumor associated transplantation antigens (TATA) that
are expressed by tumor cells and normal cells. Although chemical- , UV- or virus-induced
tumors express neo-antigens, majority of the tumors are often weakly immunogenic or
non-immunogenic. In most cases, tumor-specific transplantation Ags cannot be identified
easily. Also, some of these antigens may be secreted while others include membraneassociated molecules. The majority of tumor Ags are also present on normal cells and are
referred to as tumor associated transplantation antigens (TATA). They may be expressed
at higher levels on tumor cells when compared to normal cells. Alternatively, they may be
expressed only during development of cells and lost during adult life but re-expressed in
tumors.
Unique Tumour Specific Antigens are found only on tumour cells and not on other cells of
the host. There are several examples of unique tumour specific antigens (TSAs) include :
(a) Virally Induced Antigens :The best example of unique TSAs are those induced by
viruses. In mammals, several RNA virsuses (example: retroviruses) and DNA
viruses (example: herpes viruses) cause malignant transformation. The best example
and the greatest triumph so far in tumour immunology is that of Marek’s disease in
chickens, caused by a herpes virus. The virus infects the lymphocyte and transforms
it; a unique protein is found on the membrane of the transformed lymphocyte when
the viral DNA integrates with the host cell genome. All tumours due to this virus
carry this surface antigen and antibodies to the protein are detectable in host sera.
It is now possible to immunize animals prophylactically against Marek’s disease,
using either the whole virus or the TSA. Tumour cells induced by RNA viruses
express antigens coded for by the viral protein in addition to their own cell surface
antigens. These may be viral envelope antigens or intra viral proteins. Antigens of
virally induced tumours show extensive cross reactivity; immunization of animals
with any of these viruses provides protection against a variety of similar viruses.
Common oncogenic RNA viruses are the human T cell leukaemia virus (HTLV) in
man and the feline leukaemia virus (FeLV) in cats. In many of these oncogenic
viruses, it has been shown that viral antigens activate cellular oncogenes leading to
cell transformation. Some of these oncogene products will render malignant cells
sufficiently disparate from normal cells. This could also explain the extensive cross
reactivity between the TSAs of oncogenic viruses.
(b) Chemically or Physically Induced Tumour Antigens :Alterations in both major and
minor histocompatibility antigens on tumours have been described in chemical
carcinomas. The same mechanism is said to operate in tumours due to ultraviolet
light or radiation. Generation of an enormous variety of distinct tumour antigens
makes it unlikely that immunization against such cancers will ever be possible.
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(c) Antigens of Spontaneous Tumours: Spontaneous tumours are those that have no
known inducing agent. Though antigens differing from normal cellular antigens
have been identified, it has not been possible to characterize a unique TSA from
such tumours.
Tumor Associated Antigens ( TATA )or (TSTA)
1) Viral Antigen :
a- Viral proteins and glycoproteins
b- New antigens produced by virally infected host cells under control of viral nucleic acid
2) Tumor specific antigens :Tumor cells develop new antigen specific to their carcinogens
3) Tumor specific transplantation antigens :Tumor cells express new MHC antigens due to
alteration of normally present MHC antigens
4) Oncofetal antigens: Oncofoetal antigens ( AFP &CEA) Most oncogenes were actually
present in the host cell, where they functioned in regulated cell growth. The host cell gene
was called a proto-oncogene. When transduced by the virus and expressed under the
control of a viral promotor, the gene product contributes to the unregulated growth of the
tumour cell. Since proteins encoded by proto-oncogenes are expressed by normal cells,
their over-expression on tumour cells would qualify them as tumour-associated antigens.
Tumour cells can sometimes “switch on” genes which are associated with growth and
development of the foetus. Consequently, antigens which are associated normally with
embryogenesis and are not detectable in the adult begin to appear during tumour growth.
The prototype oncofoetal antigen is (CEA), which is an improperly glycosylated
glycoprotein found on foetal gut and human colon cancer cells, but not on normal adult
colonic cells. Such abnormal glycosylation may be the cause of the observation that certain
human gastric carcinoma cells display ABO blood group antigens different from the host
ABO blood group.CEA is useful in monitoring response to treatment ( a ) Carcinoembryonic antigens (CEA) Normally expressed during fetal life on fetal gut but there is
Reappearance in adult life in GIT, pancreas, biliary system and cancer breast (b)Alpha
fetoprotein:Normally expressed in fetal life but Reappearance in adult life;in hepatoma
Immune response to tumors
Evidence for immunity against malignancy comes mostly from experimental studies,
wherein mice were immunized by administering irradiated tumor cells or following
removal of a primary tumor challenged with the same live tumor. These animals were
found to be resistant to rechallenge with the same live tumor. While Abs may develop
against few cancers, cell-mediated immunity plays a critical role in tumor rejection. Thus,
immunity can be transferred, in most cases, from an animal, in which a tumor has
regressed, to a naive syngeneic recipient by administration of T lymphocytes. The T helper
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(Th) cells recognize the tumor Ags that may be shed from tumors and internalized,
processed and presented in association with class II MHC on antigen presenting cells.
These Th cells when activated will produce cytokines. Thus, the Th cells provide help to B
cells in Ab production. The cytokines such as IFN-γ may also activate macrophages to be
tumoricidal. Furthermore, the Th cells also provide help to tumor-specific cytotoxic T cell
(CTL) by inducing their proliferation and differentiation. The CTLs recognize tumor Ags
in the context of class I MHC and mediate tumor cell lysis. In tumors that exhibit
decreased MHC Ags, natural killer (NK) cells are important in mediating tumor rejection .
Cellular Immunity against cancers include :
 (a) T cells
 ( b )Macrophage
 ( c ) NK, LAK( Lymphokines activated Killer cell )
 ( d ) B cells and antibody dependant cellular cytotoxicity
What is the Mechanisms by which tumor escape immune defenses?
1) Reduced levels or absence of MHCI molecule on tumor so that they can not be
recognized by CTLs
2) Some tumors stop expressing the antigens These tumors are called “antigen loss
variants”
3) Production of immunosuppressive factors by tumor e.g. transforming growth factor
(TGF-β)
4) Tumor antigens may induce specific immunologic tolerance
5) Tumor cells have an inherent defect in antigen processing and presentation
6) Blocking of receptors on T-cells by specific antigen antibodies complex (after shedding of
tumor Ag) prevents them from recognizing and attacking tumor cells
7) Antigens on the surface of tumors may be masked by sialic acid-containing
mucopolysaccharides
8) Immune suppression of the host as in transplant patients who show a higher incidence of
malignancy
Immunodiagnosis in Cancer : Tumor Associated Antigens can be useful tumour markers in
the diagnosis and management of various tumours. An ideal tumour marker is released
only from tumour tissue, is specific for a given tumour type (to direct diagnostic
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assessment), is detectable at low levels of tumour cell burden, has a direct relationship to
the tumour cell burden and the marker concentration in blood or other body fluid, and is
present in all patients with the tumour. Most tumours release antigenic macromolecules
into the circulation that can be detected by immunoassay. Although useful in monitoring
patients for tumour recurrence after therapy, no tumour marker has undisputed specificity
or sensitivity for application in early diagnosis or mass cancer screening programs.
Tumor Markers
Tumor markers :They are either Tumor antigens or Tumor products (enzymes and
hormones) Tumor products are released in the serum of patients They are used to confirm
diagnosis and follow up the response to therapy
Examples of tumor markers :
Carcinoembryonic antigen (CEA) is a protein-polysaccharide complex found in colon
carcinomas and in normal foetal intestine, pancreas, and liver
α-Fetoprotein, a normal product of foetal liver cells, is also found in the sera of patients
with primary hepatoma, yolk sac neoplasms, and frequently, ovarian or testicular
embryonalcarcinoma.
β-Subunit of human chorionic gonadotropin (β-HCG), measured by immunoassay, is the
major clinical marker in women with gestational trophoblastic neoplasia, about 2/3 of men
with testicular embryonal or choriocarcinoma
Prostate-specific antigen (PSA), a glycoprotein located in ductal epithelial cells of the
prostate gland,
CA 125 is clinically useful for diagnosing and monitoring therapy for ovarian cancer
Tumor Products :
a) Hormones :
- Human chorionic gonadotrophins (HCG) are secreted
in cases of choriocarcinoma
- Thyroxin (T3 & T4) is secreted in cases of cancer
of thyroid gland
b) Enzymes :
- Acid phosphatase enzymes in cases of cancer prostate
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- Alkaline phosphatese, lipase and amylase enzymes in cases of cancer pancreas
Immunotherapy
Immunotherapy has been used as a novel mode to treat cancer. Both active and passive
means of stimulating the non-specific and specific immune systems have been employed, in
some cases with significant success .
1) Active Immunotherapy: Wherein the host actively participates in mounting an
immune response include :
a) Nonspecific activation is achieved by immunization with: i) Bacillus CalmetteGuerin (BCG) ii) Corynebacterium parvum These activate macrophages to be
tumoricidal.
b) Specific activation using vaccines: i) Hepatitis B vaccine ii) Human Papilloma virus
(HPV) vaccine & iii) Defined tumour antigen-based vaccines are among the most promising
approaches in cancer immunotherapy. An increasing number of tumour antigens have
been unequivocally identified as the target of specific T cells grown from cancer patients.
2) Passive Immunotherapy: This involves transfer of preformed Abs, immune cells
and other factors into the hosts.
a) Specific :
i) Antibodies against tumor Ags (e.g. Her2/Neu for treatment of breast cancer)
ii) Abs against IL-2R for Human T lymphotropic virus (HTLV-1)-induced adult T cell
leukemia
iii) Abs against CD20 expressed on non Hodgkin’s B cell lymphoma.
These Abs bind to tumor Ags on the cell surface and activate complement (C’) to mediate
tumor cell lysis. In addition, Fc receptor bearing cells such as NK cells, macrophages and
granulocytes may bind to the Ag-Ab complexes on tumor cell surface and mediate tumor
cell killing through Ab-dependent cell-mediated cytotoxicity.
iv) Abs conjugated to toxins, radioisotopes and anti-cancer drugs have also been used.
These enter the cells and inhibit protein synthesis. e.g. anti-CD20 conjugated to
Pseudomonas toxin or ricin toxin. There are several problems with the use of Abs
1) Abs are not efficient because the tumor Ags are associated with class I MHC Ags.
2) The tumors may shed Ag or Ag-Ab complexes. Thus, immune cells cannot mediate
tumor destruction.
3) Some Abs may not be cytotoxic.
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4) Abs may bind nonspecifically to immune cells expressing the Fc receptors which include
NK cells, B cells, macrophages and granulocytes without binding to tumor cells.
b) Non specific :
i) Adoptive Transfer of lymphocytes:
(1) Lymphokine-activated killer (LAK) cells which are IL-2 activated T and NK cells.
(2) Tumor-infiltrating lymphocytes (TIL)
ii) Dendritic cells pulsed with tumor Ags may induce tumor-specific T cell responses. As
tumor Ags are usually not known, tumor lysates are used.
iii) Cytokines ( examples ) :
(1) IL-2: Activates T cells/NK cells expressing IL-2 receptors. Used in the treatment of
renal cell carcinoma and melanoma,
(2) IFNα: Ιnduces MHC expression on tumors and used in the treatment of hairy B cell
leukemias
(3) IFN-γ: Ιncreases class II MHC expression; used in the treatment of ovarian cancers.
(4) TNF-α: Kills tumor cells.
iv) Cytokine gene transfected tumor cells may also be used which can activate T or LAK
cell-mediated anti-tumor immunity.
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