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Chapter: Microbiology and Immunology: Immunology of Transplantation and Malignancy

Tumor Immunology

Tumor immunology has been defined as part of immunology that deals with the antigens on tumor cells and the immune response to them.

Tumor Immunology

Tumor immunology has been defined as part of immunology that deals with the antigens on tumor cells and the immune response to them. As a consequence of their loss of differen-tiation, tumor cells may express developmental antigens that are usually seen only in the prenatal period. Examples of these antigens are alpha-fetoprotein and carcinoembryonic antigen. Tumors or neoplasia is said to develop when the bal-ance between cell death and renewal is disturbed in a way that numerous clones of a single cell group are produced in an uncontrolled fashion.

Features of Malignant Cells

Malignant cells show the following features:

i.               Once cells become malignant, they stop functioning normally and add to the burden on the body by competing with the normal cells for space and nutrition.

ii.               The more “undifferentiated” a cell is, the lesser its functionality and more its malignant nature.

iii.               They undergo rapid and uncontrolled division.

iv.               They lose their homing instinct and start invading the basement membrane and enter the vasculature to spread to dissimilar tissues, leading to metastasis and spread of cancer.

It has been postulated that the immune system is responsible in part for the protection of the body against the development of malignancies. At the same time, the prevalence of numer-ous cancers in immunocompetent individuals indicates that immune system has only a partial role in protecting against malignancies and also that it is not very efficient at it.

Tumor Antigens

Tumor cells also express unique molecules that can be classi-fied into two groups:

i.               Tumor-specific antigens

ii.               Tumor-associated transplantation antigens

 Tumor-specific antigens

The tumor-specific antigens (TSAs), also called tumor-specific transplantation antigens, are unique to tumors. They are not found on other cells of the body. They are usually the products of mutated genes seen in the cancer cells. Cytosolic processing of the abnormal proteins yields peptides that are unique and when presented by the appropriate MHC class I molecules elicit a cell-mediated immune response.

Various physical and chemical carcinogens cause malignan-cies by inducing mutation in key genes involved in modulating cell growth. Ras proto-oncogene products including the p21 Ras pro-teins and other related gene products are an example of TSAs. Ras proteins bind guanine nucleotides (GTP and GDP) and possess intrinsic GTPase activity. The mutations associated with Ras genes in malignant cells appear to cause a single amino acid substitu-tions at specific positions (12, 13, or 61), which results in increased enzymatic activity of the gene product. As a consequence, the cells acquire transforming capacity. Moreover, these products are also recognized as foreign antigens by the cellular immune response.

Another mode through which the tumor cells may express unique and novel antigens “is by” integration with proviral genomes. These virus-induced tumors usually have their genome integrated with proviral genome, hence the proteins encoded and expressed are sometimes novel and recognized by the cellular immune response. Viruses that have been implicated in tumorigenesis include Epstein–Barr virus (EBV), hepatitis B virus (HBV), hepatitis C virus (HCV), etc.

 Tumor-associated transplantation antigens

Tumor-associated transplantation antigens (TATAs) are the other class of tumor antigens. These antigens are expressed by (a) tumor cells and also by (b) normal cells at low levels or only dur-ing the process of differentiation. The expression of these anti-gens is considerably derepressed or enhanced after the process of malignant transformation. TATAs can be of the following types:

1.Tumor-associated carbohydrate antigens: They representabnormal form of mucin-associated antigen detected in breast and pancreatic cancers.


2.Differential antigens: These include CD10 and prostate-specific antigens (PSA). The latter is used as a diagnostic indica-tor in prostatic cancer.

3. Oncofetal antigens: These antigens are found in embryonicand malignant cells but are absent in normal adult cells. Alpha-fetoprotein and carcinoembryonic antigens are examples of this antigen, which are found in hepatomas and colonic cancers, respectively. Silent tumor-associated genes are not expressed in normal cells but are actively transcribed in tumor cells. Tissue-specific genes or differentiation genes are present in the surface of normal cells or may be shed to the circulation, but the levels of expression are usually very low in normal cells. This finds practi-cal application in the diagnosis of malignancies as illustrated by the assay of PSA for the diagnosis of carcinoma of prostate.

PSA: It is a kallikrein-like serine protease produced exclusively bythe epithelial cells in the prostate gland. The antigen is detectable at relatively high levels in seminal plasma and at very low levels in the serum of healthy men. The assay of serum PSA levels is a very useful marker of prostate carcinoma, perhaps the most meaning-ful serum marker for neoplasia. In healthy men, the levels of PSA vary between 0.65 0.66 ng/mL at ages 21–30 and 1.15 0.68 ng/mL at ages 61–70. Significantly elevated levels are demon-strated in 63–86% of patients with prostatic carcinoma, depend-ing on the stage. In essence, antigens of tumors that are capable of eliciting an immune response may be one of the following nature:

·           First, these antigens are uniquely expressed by tumor cells alone. Also, there are the products of genes that have been mutated during the process of transformation, leading to the expression of abnormal products.

·           Second, certain antigens expressed by tumors are present only when normal cells are undergoing the process of dif-ferentiation and these are also readily recognized by the immune system.

·           Finally, the antigens that are overexpressed by the tumor cells elicit a good immune response.

Immune Reactions against Tumors

Tumor antigens are capable of eliciting a comprehensive immune response involving both the cellular and humoral immune responses.

 Cellular immune responses

T lymphocytes play an important role in tumor immunity. They act both as cytotoxic effector cells and as central modulating cells. Through these effector cells, they control the specific cell-mediated antitumor immune responses and upregulate non-specific killing mechanisms. The activation of T lymphocytes by tumor cell products as a consequence of antigen recognition may result in the secretion of nonspecific immunoregulatory factors.

·           These factors are capable of “upregulating” the tumor-killing function of mononuclear phagocytes, NK cells, and granulocytes.

·           These factors also enhance the ability of NK cells and mono-cytes to participate in ADCC against tumor cells.

·           Macrophages also play an important role in tumor response. Clustering of macrophages around tumor cells is associated with tumor regression and seen in the case of numerous cancers.

 Humoral immune responses

B lymphocytes produce tumor-specific antibodies, which may induce complement-dependent cytotoxicity of tumor cells or may mediate ADCC. ADCC can be mediated by a variety of cells expressing Fc receptors (NK cells, monocytes or macrophages, and granulocytes) by recognizing and destroying IgG-coated tumor cells.


The emergence of cancer cells within the body may not be a rare or unusual event at all. Of the trillions of normal cells found in the body, several hundred per day may be undergoing malignant degeneration in response to the cancer-promoting stimuli. The immune system may possibly play a significant role in halting the growth of these cells and preventing the development of overt malignancy.

The concept of immune surveillance was initially put for-ward by Ehrlich, and later on modified by Thomas and Burnet. Ehrlich first suggested that though cancer cells frequently arise in the body, they are recognized as foreign and eliminated. Later, Burnet postulated the immunosurveillance theory. He suggested that the immune system routinely patrols the cells of the body and upon recognition of a cell or a group of cells that has become cancerous attempts to destroy them, thus pre-venting the growth of some tumors.

Immunotherapy of Cancer

Immunotherapy of cancer can be considered as the following two broad groups:

i.               Antigen-nonspecific treatment

ii.               Antigen-specific treatment

 Antigen-nonspecific treatment

This includes treatment with various nonspecific immune modulators.

·           Bacillus Calmette–Guérin (BCG) vaccine has been shown to possess antitumor activity. The vaccine when injected directly into certain solid tumors may cause regression of tumor. Antitumor effect of tumor is believed to be due to activation of macrophages and NK cells. The BCG therapy has been reported to be beneficial in treatment of bladder cancer, malignant melanomas, stage I lung cancer, and cer-tain leukemias.

·           Corynebacterium parvum also possesses antitumor activities.Its antitumor effect is due to its ability to stimulate macro-phages and B cells. It shows a synergistic effect when used in conjunction with cyclophosphamide. It is found to be useful in treatment of metastatic breast cancer and various types of lung cancer.

·           Other nonspecific immune modulators include (i) dinitro-chlorobenzene (DNCB), evaluated in squamous and basal carcinoma, (ii) levamisole for stimulating cell-mediated immunity and macrophage function, (iii) interferon to stim-ulate NK cell function, (iv) cytokine IL-2 to stimulate killing of cancer cells by cytotoxic T cells, (v) NK cells, and mac-rophages, thymic hormones to restore T cell function, and (vi) tuftsin to stimulate phagocytic cells.

 Antigen-specific treatment

Antigen-specific treatment includes (a) vaccination with tumor antigen, (b) treatment with transfer factor, (c) treatment with immune RNA, (d) treatment with monoclonal antibodies raised against tumor-associated antigens (TAAs) given alone or in conjunction with cytotoxic drug, and (e) modification of tumor antigenicity by treatment with neuraminidase.

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