Tumor Immunity - A Systematic Review

Introduction Ehrlich proposed that autologous cancer cells may be detected by the immune system, acting as a "positive mechanism" that could eliminate changed cells. This led to the theory that tumours are not entirely "self." One genetically harmed progenitor cell undergoes clonal proliferation before becoming a tumour. Formalizing this concept, Lewis Thomas and Macfarlane Burnet later coined the term "immune surveillance" to refer to the identification and elimination of newly developing cancer cells. The development of malignancies indicates the ineffectiveness of immunological monitoring; yet, the possibility that other tumours could have been averted does not disappear just because some manage to elude such policing. The immune system plays a critical role in molecular recognition, self-pathogen elimination, and self-versus-non-self-differentiation. The immune system may be overstimulated for clinical control even if cancer cells avoid detection.¹

Types of Genes Controlling Cancer

Proto-oncogenes that promote growth, tumour suppressor genes that prevent tumour growth, genes controlling programmed cell death, and genes involved in DNA repair.²

Tumor antigens

Based on their original modalities of expression, they were essentially split into two groups: tumor-specific antigens, which are only found on cancer cells and not on any normal cells, and antigens associated with malignancies (found on certain normal cells as well as cancer cells). An important development in the study of cancer immunology was the development of techniques for identifying the antigens present in tumours that were recognized by cytotoxic T lymphocytes (CTLs), the immune system's main defense mechanism against malignancies.³

Classification of Tumor Antigens Based on their Molecular Structure and Source

• Products of mutated oncogenes and tumor suppressor genes

• Products of the other mutated genes

• Overexpressed or aberrantly expressed cellular proteins

• Tumor antigens produced by oncogenic viruses

• Oncofetal antigens

• Altered cell surface glycolipids and glycoproteins

• Cell type-specific differentiation antigens⁴

Products of mutated oncogenes and tumor suppressor genes

Genetic alterations brought on by neoplastic conditions produce cell surface antigens that the immune system misinterprets as being part of the self. Antigens originate from oncoproteins and mutant tumour suppressors. Different tumour antigens are produced by CDK4, P53, RAS, and beta-catenin. Because mutant genes are exclusively present in malignancies, mutant peptides are only expressed in tumours. Furthermore, unmutated oncogenes like the HER2/NEU oncogene for breast cancer are overexpressed.⁵

Products of the other mutated genes

Genes with no known function and whose byproducts are unrelated to the changed phenotype mutate as a result of genetic instability. Consequently, the products of these genes may function as antigens for tumours. Mutated cellular proteins are more commonly found in animal malignancies brought on by radiation or chemical carcinogens. They elicit an immune response since there is no self-tolerance to them.³

Overexpressed or aberrantly expressed cellular proteins

Genes whose byproducts are unrelated to the changed phenotype and whose function is unknown mutate as a result of genetic instability. Thus, the metabolites of these genes may function as antigens against tumours. Mutated cellular proteins have been found more often in animal malignancies caused by radiation or chemical carcinogens. There is an immune reaction to them as there is no self-tolerance.³

Tumor antigens produced by oncogenic viruses Proteins produced by oncogenic viruses, including human papillomavirus (HPV), Epstein-Barr virus (EBV), and hepatitis B virus (HBV), are recognized by the immune system as foreign compounds. Cytotoxic lymphocytes have the capacity to recognize the antigens on viruses and eliminate cancer cells that have been infected by them. In order to prevent female cervical cancer, for example, vaccines against HPV antigens are helpful.³

Oncofetal antigens

Nevertheless, this gene is not expressed during embryogenesis in normal adult tissues. These antigens are reexpressed in colon and liver cancers because the genes encoding them are depressed. Antibodies against onco-fetal antigens can be generated to recognize these antigens. Since they are not entirely tumor-specific, they can serve as serum cancer indicators.⁵

Altered cell surface glycolipids and glycoproteins

Glycolipids and surface glycoproteins are expressed in abnormal forms and at higher than normal levels. They are employed in the development of cancer medicines and as diagnostic markers for gangliosides, blood group antigens, and mucins, among other things. To name a few, there are malignancies of the pancreas and biliary system that express CA-19-9, ovarian tumours that express CA-125, and breast cancers that express Mucin -1 (MUC-1). On the other hand, in breast ductal carcinomas, the molecule expresses unpolarizedly and possesses unique tumor-specific peptide and carbohydrate epitopes.

Since these epitopes increase T cell and antibody responses in cancer patients, they may be used as candidates for tumour vaccines.⁶

Cell type specific differentiation antigens

These antigens, which are specific to different lineages, are important. They are also referred to as differentiation antigens. They facilitate the identification of the primary tumour tissue and act as targets for immunotherapy. For example, B-cell lymphoma. In hosts with malignancies, these differentiation antigens do not elicit immune responses since they are often normal self-antigens.⁷

Antitumor Effector Mechanisms

Antibodies against tumours can be generated; however, there is no proof that they serve any protective purpose in a physiological setting. In vivo, cell-mediated immunity is the main anti-tumor tactic. The anticancer effector mechanisms are as follows:

Cytotoxic T lymphocytes

They seem to have a preventative impact, particularly when it comes to viruses-related cancers (e.g., HPV-induced tumours, EBV-induced Burkitt lymphoma). The notion that T cells are more important in immunizing against human cancers than previously believed is raised by the availability of Major histocompatibility complex (MHC)-restricted CD8+ cells that are capable of killing autologous tumour cells in human malignancies.⁸

Natural killer cells

Natural killer (NK) cells are immune cells that have the ability to eliminate cancer cells without first becoming sensitized, making them potentially the first line of defense against these cells. After being stimulated with IL-2, NK cells have the ability to lyse a wide range of human cancers, including several that don't seem to be T cell immunogenic. T and NK cells both offer complementary anticancer strategies. Malignancies that are unable to express MHC class I antigens may activate NK cells because they are inhibited by the recognition of normal autologous class I molecules. NK cells have a wide range of triggering receptors that originate from many gene families.⁹ Significant activating receptors, NKG2D proteins are expressed on certain T cells and NK cells. They are able to discriminate between antigens produced on tumour cells by stress and cells whose DNA has been damaged and which may potentially grow into cancer.⁹

Macrophages

Macrophages may cooperate in the antitumor response because interferon, a cytokine secreted by cells and natural killer cells, is a strong macrophage activator. Activated macrophages may kill tumours (TNF) by secreting tumour necrosis factor or by employing techniques similar to those employed to kill bacteria (such as the production of reactive oxygen metabolites).⁸

Humoral mechanisms

Despite the paucity of evidence substantiating antitumor antibody protection against spontaneous malignancies, monoclonal antibodies directed against tumour cells may have therapeutic value. A monoclonal antibody directed against the B cell surface protein CD20 is commonly used in the treatment of several non-Hodgkin lymphomas.¹⁰

Immune Surveillance and Immune Evasion by Tumors

Immune monitoring is most clearly justified by the greater incidence of cancer in immunocompromised hosts. It has been observed that 5% of those with congenital immunodeficiencies may get cancer, which is approximately 200 times more common than in those without such immunodeficiencies. Immunosuppressed transplant patients and those with acquired immunodeficiency syndrome both experience a corresponding increase in cancer cases. Remarkably, most (though not all) of these neoplasms are lymphomas, often lymphomas derived from activated B cells. One prime example is X-linked lymphoproliferative disease. When affected boys get EBV, the typical self limited form of infectious mononucleosis does not occur; instead, the virus progresses to a lethal form of infectious mononucleosis or, worse still, malignant lymphoma.^8,11

Several escape mechanisms have been proposed

Selective outgrowth of antigen-negative variants

Loss or reduced expression of histocompatibility molecules

Immunosuppression

Antigen masking

Down-regulation of co-stimulatory molecules

Selective outgrowth of antigen-negative variants

As the cancer grows, highly immunogenic subclones might be eliminated. Research indicates that tumours growing in immunosuppressed mice express identifiable antigens, which trigger the immune system in normal mice to eradicate the tumours. Conversely, tumours growing in immunocompetent mice do not exhibit these antigens and are considered non-immunogenic.¹²

Loss or reduced expression of histocompatibility molecules

Class HLA (human leukocyte antigen) - It is possible that cancer cells don't express at normal levels, which makes them invisible to CTLs. But these cells have the ability to activate NK cells.¹²

Immunosuppression

Numerous carcinogenic agents, including chemicals and ionizing radiation, suppress the immune system of the host. Furthermore, immunosuppressive qualities may be present in malignancies or tumour products. For example, transforming growth factor (TGF), which has strong immunosuppressive effects, is released by many tumours. Sometimes tumour immunity is inhibited by the immune response triggered by the tumour. Several mechanisms behind this inhibition have been described. For example, the detection of cancer cells may trigger the engagement of the T cell inhibitory receptor CTLA-4 or the activation of regulatory T cells that suppress immunological responses. Even more dangerously, certain tumours express FasL, which combines with immune cell surface Fas to induce apoptosis.¹³

Antigen masking

A greater layer of glycol-calyx molecules, such as sialic acid-containing mucopolysaccharides, is developed by many cancer cells in comparison to normal cells. The presence of this thick layer may prevent immune cells from reaching molecules that present antigens, preventing the detection of the antigen and any cell-killing activity.¹²

Downregulation of co-stimulatory molecules

Co-stimulatory substances are required to elicit potent T cell responses. Many malignancies have diminished expression of these co-stimulatory molecules.¹²

Conclusion

Over the last decade, there has been a notable advancement in our comprehension of the functioning of the immune system. Consequently, we now know that the immune system may be able to identify "altered-self" while cancer is growing, in addition to its ability to discriminate between self and non-self. Endogenous anti-tumor immune responses are certainly reduced by a variety of distinct routes in some settings, even though these linkages may limit the formation or growth of specific tumours. Therefore, continued study into the operation of the innate and adaptive immune systems is essential to the application of treatment techniques. In fact, a better understanding of the immune system's mechanisms and how it interacts with the tumour environment is essential for the development of effective treatment methods for cancer immunotherapy.

Conflict of Interest

None