Tumor Immunology – Definition, features

• Tumor immunology has been defined as the subfield of immunology that focuses on tumour cell antigens and the immune response to them.
• As a result of their loss of differentiation, tumour cells may express developmental antigens that are typically only detected during prenatal development. These antigens include alpha-fetoprotein and carcinoembryonic antigen as examples.
• Tumors or neoplasia are said to occur when the balance between cell death and renewal is upset, resulting in the uncontrolled multiplication of clones of a single cell group.
• A benign tumour cannot develop indefinitely and does not significantly invade the healthy surrounding tissue.
• Malignant tumours are those that continue to grow and become increasingly invasive; cancer refers especially to malignant tumours.
• In addition to uncontrolled development, malignant tumours demonstrate metastasis; in this process, small clusters of cancerous cells break away from a tumour, enter blood or lymphatic arteries, and are transported to other tissues, where they continue to proliferate. Thus, a primary tumour at one location can give rise to a secondary tumour in a different location.

Features of Malignant Cells 

Malignant cells exhibit the following characteristics:

• Once cells become cancerous, they cease to function normally and increase the body’s burden by competing with healthy cells for space and nutrients.
• The more “undifferentiated” a cell is, the less functional it is and the more cancerous it is.
• They undergo unregulated and rapid division.
• They lose their homing instinct, invade the basement membrane, and penetrate the vasculature to spread to different tissues, resulting in cancer metastasis and dissemination.

It has been hypothesised that the immune system is partially responsible for protecting the body from the development of cancers. In addition, the presence of multiple tumours in immunocompetent individuals suggests that the immune system has a limited function in defending against cancer and is not particularly effective at it.

Tumor Antigens 

Additionally, tumour cells express unique chemicals that can be divided into two categories:

1. Tumor-specific antigens
2. Tumor-associated transplantation antigens

Tumor-specific antigens

• Tumor-specific antigens (TSAs), also known as antigens for tumor-specific transplantation, are unique to malignancies. They are not seen on any other bodily cells.
• Typically, they are the result of altered genes found in cancer cells. The aberrant proteins undergo cytosolic processing to generate unique peptides that, when presented by the proper MHC class I molecules, induce a cell-mediated immune response.
• Diverse physical and chemical carcinogens induce mutations in essential genes involved in regulating cell growth, hence causing cancer. TSAs include Ras proto-oncogene products such as the p21 Ras proteins and other related gene products.
• Ras proteins possess intrinsic GTPase activity and bind guanine nucleotides (GTP and GDP).
• The mutations linked with Ras genes in malignant cells appear to arise in the substitution of a single amino acid at certain locations (12, 13, or 61), which increases the gene product’s enzymatic activity.
• As a result, the cells acquire the ability to change. Moreover, the cellular immune response recognises these substances as foreign antigens.
• Integration with proviral genomes is an additional method by which tumour cells may express novel and distinct antigens.
• Typically, the genome of these virus-induced malignancies is integrated with the proviral genome; hence, the proteins produced and expressed are occasionally unique and recognised by the cellular immune system.
• Viruses such as Epstein–Barr virus (EBV), hepatitis B virus (HBV), and hepatitis C virus (HCV) have been linked to cancer.

Tumor-associated transplantation antigens

The other type of tumour antigens are tumor-associated transplantation antigens (TATAs). These antigens are expressed at low levels or exclusively during the differentiation process by (a) tumour cells and (b) normal cells. After the malignant transformation process, the expression of these antigens is significantly depressed or increased. TATAs are available in the following forms:

1. Tumor-associated carbohydrate antigens: They are a variant of the mucin-associated antigen seen in breast and pancreatic tumours. 
2. Differential antigens: CD10 and prostate-specific antigens are examples (PSA). In prostate cancer, the latter is employed as a diagnostic sign.
3. Oncofetal antigens: These antigens are present in embryonic and cancerous cells, but not in normal adult cells. This antigen is represented by alphafetoprotein and carcinoembryonic antigens, which are detected in hepatomas and colon malignancies, respectively. Cancer-associated genes that are silent in normal cells are actively translated in tumour cells. There are tissue-specific or differentiation genes on the surface of normal cells or they may be lost into the circulation, but their expression levels are typically quite low. This has practical relevance in the diagnosis of cancers, as exemplified by the PSA test for the diagnosis of prostate cancer.

PSA

It is a kallikrein-like serine protease generated solely by prostate gland epithelial cells. The antigen is detected at reasonably high concentrations in seminal plasma but at extremely low concentrations in the serum of healthy males. The measurement of serum PSA levels is a very useful indicator of prostate cancer, and is possibly the most significant serum marker for neoplasia. PSA readings in healthy men range from 0.65 to 0.66 ng/mL between ages 21 and 30 to 1.15 to 0.68 ng/mL between ages 61 and 70. Depending on the stage, 63–86% of patients with prostatic cancer exhibit significantly increased levels. Antigens of tumours capable of triggering an immune response may essentially be one of the following types:

• First, these antigens are expressed exclusively by tumour cells. In addition, there are products of genes that have undergone mutations during the transformation process, resulting in the expression of aberrant products.
• Second, certain antigens expressed by tumours are only present when normal cells are differentiating, and the immune system readily recognises these antigens as well.
• The antigens that are overexpressed by tumour cells finally induce an effective immune response.

Immune Reactions against Tumors 

Tumor antigens are capable of triggering an immune response that includes both the cellular and humoral immune responses.

Cellular immune responses

T cells are essential for tumour immunity. These cells serve as both cytotoxic effector cells and central modulator cells. They regulate particular cell-mediated antitumor immune responses and upregulate nonspecific killing mechanisms via these effector cells. As a result of antigen recognition, the activation of T lymphocytes by tumour cell products may result in the production of nonspecific immunoregulatory molecules.

• These substances can “upregulate” the function of mononuclear phagocytes, NK cells, and granulocytes to kill tumours.
• These substances also promote the participation of NK cells and monocytes in ADCC against tumour cells.
• In addition, macrophages play a crucial part in the tumour response. The clustering of macrophages around tumour cells is linked to tumour regression and is observed in a variety of malignancies.

Humoral immune responses 

• B lymphocytes generate tumor-specific antibodies, which may trigger complement-dependent cytotoxicity or mediate ADCC in tumour cells.
• NK cells, monocytes or macrophages, and granulocytes that express Fc receptors can cause ADCC by identifying and killing IgG-coated tumour cells.

Immunosurveillance

• The development of cancer cells within the body may not be a rare or exceptional occurrence. Several hundred each day of the body’s trillions of normal cells may develop malignant degeneration in response to cancer-promoting stimuli.
• The immune system may play an important role in inhibiting the proliferation of these cells and preventing the emergence of overt cancer.
• Ehrlich introduced the concept of immune surveillance, which was later developed by Thomas and Burnet.
• First proposed by Ehrlich, even though cancer cells develop regularly in the body, they are identified as foreign and removed.
• Burnet later proposed the immunosurveillance idea. He proposed that the immune system routinely monitors the body’s cells and, upon recognising a malignant cell or group of cells, strives to eliminate them, so preventing the growth of some tumours.

Immunotherapy of Cancer 

Immunotherapy for cancer can be categorised into two broad categories:

• Antigen-nonspecific treatment
• Antigen-specific treatment

Antigen-nonspecific treatment

This includes the utilisation of nonspecific immune modulators.

• It has been demonstrated that the Bacillus Calmette–Guérin (BCG) vaccination has anticancer efficacy. When injected directly into certain solid tumours, the vaccine may induce tumour regression. It is hypothesised that the antitumor action of the tumour is related to the activation of macrophages and NK cells. It has been reported that BCG therapy is effective in treating bladder cancer, malignant melanomas, lung cancer at stage I, and some leukemias.
• Corynebacterium parvum possesses anticancer properties as well. Due to its capacity to excite macrophages and B cells, it has anticancer effects. It demonstrates a synergistic effect when used with cyclophosphamide. It has been reported to be effective in the treatment of metastatic breast cancer and other lung cancer types.
• Other nonspecific immune modulators include (i) dinitrochlorobenzene (DNCB), evaluated in squamous and basal carcinoma, (ii) levamisole for stimulating cell-mediated immunity and macrophage function, (iii) interferon to stimulate NK cell function, (iv) cytokine IL-2 to stimulate killing of cancer cells by cytotoxic T cells, (v) NK cells, and macrophages, thymic hormones to restore T cell function, and (vi) tuftsin to stimulate phagocytic cells.

Antigen-specific treatment

• (a) vaccination with tumour 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 combination with cytotoxic drug, and (e) modification of tumour antigenicity by treatment with neuraminidase.