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Dr Abdul Ghaffar |
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READING: Roitt, Brostoff and Male: Immunology, 6th Ed., Chapt. 18. |
IMMUNOLOGY - CHAPTER EIGHTEEN TUMOR IMMUNOLOGY
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TEACHING
OBJECTIVES |
Evidence for immune reactivity to tumors There is a lot of evidence that tumors can elicit an immune response. Such evidence includes:
Tumor associated antigens In order for the immune system to react against a tumor, the latter must have antigens that are recognized as foreign. A number of alterations occur in the cell during tumorigenesis (e.g., enzymes, receptors, membrane antigens, etc.). Most relevant from the point of view of immuno-surveillance are surface membrane molecules which might be antigenically novel or suppression of membrane proteins that are essential for immune recognition and activation. In animals, most chemically- or physically- induced tumors or or those produced as a result of a virus, have neo-antigens. Spontaneously occurring tumors are often weakly immunogenic or non-immunogenic. Antigenic changes observed in malignant cells include reappearance of fetal antigens (onco-fetal antigens), and expression of unique antigens not expressed by normal cells. Some of these antigens may be secreted while others are membrane-associated molecules. Neo-antigens that contribute toward tumor rejection are referred to as tumor associated transplantation antigens (TATA). Onco-fetal antigens Onco-fetal antigens may appear due to de-repression of genes that were only expressed early in life. Two major onco-fetal antigens are alpha-fetoprotein (AFP) and carcino-embryonic antigen (CEA ). AFP is produced only as a secreted protein whereas CEA is found both on cell membranes and in secreted fluids. Since secreted antigens contribute little toward immunity against tumors, the role of these neo-antigens in immuno-surveillance is questionable. Alpha-fetoprotein The normal range of AFP
concentrations in humans is 0-20 ng/ml. This level rises considerably in patients
with hepatomas and non-seminal testicular carcinoma. A 5-fold or higher rise in
this protein is used for monitoring hepatomas and testicular cancers. AFP level
may also be raised in some non-malignant conditions, such as cirrhosis, in
hepatitis and other forms of liver damage. |
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Figure 1 |
Carcinoembryonic antigen CEA levels in normal people range up to 2.5 ng/ml, but they increase significantly in certain malignancies, particularly colo-rectal cancers.They may also rise in some non-malignant conditions (such as chronic cirrhosis, pulmonary emphysema and heavy smoking). Levels that are 4-5 times normal have been used to predict recurrence of colo-rectal tumors. Tumor associated transplantation antigens (TATA) on viral tumors A number of viruses cause different
types of tumors in animals (SV-40 virus, adenovirus, Rous sarcoma virus, Friend
erythroleukemic virus, Moloney Rauscher and
Gross viruses). Viruses are involved or suspected to be involved in some human
malignancies (HTLV-1 in leukemia, hepatitis-B virus in hepatic carcinoma,
papilloma virus in cervical cancer). Virus-induced tumors express cell surface
antigens (distinct from antigens of the virion itself) which are shared by all tumors
induced by the same virus. These antigens are characteristic of the
tumor-inducing virus, regardless of tissue origin of the tumor or animal species
in which the tumor exists (Figure 1). More information on tumor viruses can be
found in the here |
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Figure 2 |
Tumor associated transplantation antigens on chemically-induced tumors Chemically-induced tumors are
different from virally-induced tumors in that they are extremely heterogeneous
in their antigenic characteristics. Thus, any two tumors induced by the same
chemical, even in the same animal, rarely share common tumor specific antigens
(Figure 2). These unique antigens on chemically-induced tumors are referred to
as tumor specific transplantation antigens (TSTA).
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Immunity against tumors Evidence for immunity against malignancy comes mostly from experimental tumors, although there is ample evidence for anti-tumor immune reactivity in humans. In experimental studies, animals can be immunized by administering inactivated tumor cells or by removal of a primary tumor. Also, immunity can be transferred from an animal, in which a tumor has regressed, to a naive animal by injection of lymphocytes (T cells). All components of the immune system (non-specific and specific; humoral and cellular) can affect the growth and progression of a tumor. Escape from immuno-surveillance A number of mechanisms have been suggested for the escape of malignant cells from host immuno-surveillance. Tumors may not express neo-antigens that are immunogenic or they may fail to express co-stimulatory molecules for the activation of T-cells. In addition, certain tumors are known to lack or be poor expressers of MHC antigen. Another reason for failure of immunosurveillance may be the fact that in the early development of a tumor, the amount of antigen may be too small to stimulate the immune system and, due to the rapid proliferation of malignant cells, the immune system is quickly overwhelmed. In addition, some tumors may evade the immune system by secreting immunosuppressive molecules and others may induce suppressor cells. Also, some tumors may shed their unique antigens which block antibodies and T cells from reacting with malignant cells.
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Use of tumor neo-antigens in patient management The presence of neo-antigens on tumor cells has been exploited for both diagnostic and therapeutic purposes. Immuno-diagnosis Monoclonal antibodies labeled with radioisotope have been used for in vivo detection of relatively small tumor foci. Antibodies have also been used in vitro to identify the cell origin of undifferentiated tumors, particularly of lymphocytic origin. Also, immuno-histological staining is used to confirm suspected metastatic foci, especially in bone marrow.
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Immunotherapy Immunotherapy has been used as adjunct to traditional treatments. Both active and passive means of stimulating the non-specific and specific immune systems have been employed, in some cases with significant success (Table 1).
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A variety of immunopotentiating
agents (biological response modifiers) are used to enhance anti-tumor immunity.
They include bacterial products, synthetic chemicals and cytokines (Table 2).
Most of these agents exert their effects by activating macrophages and natural
killer (NK) cells,
eliciting cytokines or enhancing T-cell functions.
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| A number of cytokines have been
used to potentiate the immune function of the host since the discovery that
these cytokines have potent and selective effects on certain components of the
immune system (Table 3).
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Figure 3 |
Monoclonal anti-tumor antibodies have been used in different forms for the treatment of cancer, either because of their direct effect or as vehicles to target anti-cancer drugs, toxins and the non-specific components of the host's immune system to the site of tumor (Figure 3). In addition, such specific antibodies are also used in the diagnosis of metastatic lesions, otherwise not detectable by conventional radiologic means. | ||||||||||||||||||
Return to the Department of Microbiology and Immunology Site Guide |
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page copyright 2004, The Board of Trustees of the University of South
Carolina |
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